From metabolism to malignancy: the multifaceted role of PGC1α in cancer

PGC1α, a central player in mitochondrial biology, holds a complex role in the metabolic shifts seen in cancer cells. While its dysregulation is common across major cancers, its impact varies. In some cases, downregulation promotes aerobic glycolysis and progression, whereas in others, overexpression escalates respiration and aggression. PGC1α’s interactions with distinct signaling pathways and transcription factors further diversify its roles, often in a tissue-specific manner. Understanding these multifaceted functions could unlock innovative therapeutic strategies. However, challenges exist in managing the metabolic adaptability of cancer cells and refining PGC1α-targeted approaches. This review aims to collate and present the current knowledge on the expression patterns, regulators, binding partners, and roles of PGC1α in diverse cancers. We examined PGC1α’s tissue-specific functions and elucidated its dual nature as both a potential tumor suppressor and an oncogenic collaborator. In cancers where PGC1α is tumor-suppressive, reinstating its levels could halt cell proliferation and invasion, and make the cells more receptive to chemotherapy. In cancers where the opposite is true, halting PGC1α’s upregulation can be beneficial as it promotes oxidative phosphorylation, allows cancer cells to adapt to stress, and promotes a more aggressive cancer phenotype. Thus, to target PGC1α effectively, understanding its nuanced role in each cancer subtype is indispensable. This can pave the way for significant strides in the field of oncology.


Introduction
The peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1a) is a pivotal transcriptional coactivator with multifaceted roles in regulating cellular energy metabolism and mitochondrial biogenesis (1).Since its first identification as a binding partner of the nuclear receptor peroxisome proliferator-activated receptor gamma (PPARa) in 1998, the significance of PGC1a in orchestrating diverse metabolic pathways has become increasingly evident (2,3).Its functions include mitochondrial biogenesis, fatty acid oxidation, gluconeogenesis, and oxidative phosphorylation (4).
The versatility of PGC1a is emphasized by its ability to interact with a multitude of transcription factors and coactivators (5,6).This enables PGC1a to exert intricate control over the expression of genes relevant to these pathways.As the cornerstone of mitochondrial biogenesis (7), PGC1a can augment the number and activity of mitochondria.This amplification enhances cellular energy production and adaptability, ensuring a balance between energy homeostasis and the response to shifts in energy demands.Beyond its metabolic functions, PGC1a is pivotal in processes such as cell growth, differentiation, and survival (8), underscoring its role in preserving cellular integrity and function.The prominence of PGC1a in physiological processes implies its potential involvement in pathologies.Indeed, perturbations in PGC1a expression or activity have been linked to a spectrum of diseases, ranging from neurodegenerative disorders (9) and metabolic syndromes to cardiovascular diseases (10).Notably, emerging evidence suggests a role for PGC1a in cancer pathogenesis (11).Its dysregulation has been implicated in metabolic reprogramming and disease progression across a variety of malignancies, both solid and hematological (1).
Unfortunately, challenges exist in managing the metabolic adaptability of cancer cells and refining PGC1a-targeted approaches.There is a need to decode the intricate molecular ties of PGC1a's interactions with cancer cells.This is a critical step in comprehending both PGC1a's multifaceted involvement in cancer and the ability to use this knowledge for cancer prevention and treatment.Therefore, this review aims to collate and present the current knowledge on the expression patterns, regulators, binding partners, and roles of PGC1a in diverse cancers.We examined PGC1a's tissue-specific functions and elucidated its dual nature as both a potential tumor suppressor and an oncogenic collaborator.A comprehensive understanding of PGC1a's intricate relationship with cancer metabolism could pave the way for novel biomarker identification and therapeutic interventions against this pervasive global health challenge.We hope that this review will serve as a foundational guide for researchers interested in the further exploration of this domain.

Structure and functions of PGC1a
The PGC1a gene, located on chromosome 4 at the 4p15.1 position, features several functional domains crucial for its activity (3).These domains include the N-terminal transcriptional coactivatory domains, which facilitate interactions with various transcription factors; a central inhibitory domain that moderates its coactivatory functions; and an RNA recognition motif (RRM) located at the C-terminus.The N-terminal region is particularly significant for its role in engaging with nuclear receptors such as peroxisome proliferator-activated receptor gamma (PPARg), nuclear respiratory factor 1 (NRF1), and estrogen-related receptor alpha (ERRa) (1,12).These interactions are essential for the transcriptional regulation of genes that play a role in mitochondrial functionality and oxidative metabolism.Upon activation, PGC1a primarily functions by coactivating nuclear receptors and other transcription factors, thereby promoting the expression of genes related to energy metabolism (13).This gene is fundamental to the adaptation to changing metabolic demands during shifts in nutrient availability or energy requirements.Specifically, PGC1a enhances mitochondrial replication, respiratory capacity, and oxidative phosphorylation, which collectively increase cellular energy production (14).The regulation of its activity involves various post-translational modifications and protein interactions, allowing for a responsive adjustment to cellular energy conditions (15,16).Through these multifaceted roles and complex regulatory mechanisms, PGC1a acts as a central regulator of metabolic processes, highlighting its importance in both normal physiology and various pathological conditions, including cancer.

Roles of PGC1a in cancer cells
PGC1a is an important gene that regulates metabolism in cancer cells, controlling pathways like glycolysis, tricarboxylic acid (TCA) cycle and fatty acid synthesis etc.But the interesting thing is its actual role differs a lot between different cancer typessometimes it suppresses tumors, but other times it promotes cancer growth instead!This depends on the complex interplay between various intracellular signaling pathways.PGC1a closely interacts with molecules like b-catenin, AMP-activated protein kinase (AMPK), and can modulate downstream gene expression based on these upstream signals.So, it acts like a central integrator of signals that reprogram metabolism.Its expression and functions are super tissue-specific.For example, from the latest studies, PGC1a expression is upregulated in ovarian cancer (OC), colorectal cancer (CRC), gastric cancer (GC), nasopharyngeal (NPC) and cholangiocarcinoma (CCA), while downregulated in thyroid cancer (TC), liver cancer and renal cancer.However, in some types of cancers, like melanoma, prostate and breast cancer, low and high expressions of PGC1a are coexisted (Figure 1).PGC1a also reshapes the tumor microenvironment by coordinating metabolic crosstalk between cancer cells and immune cells.Targeting PGC1a could potentially help overcome therapeutic resistance, but overcoming metabolic plasticity of cancer cells remains a big challenge!Here, we elucidate the mechanisms of PGC1a from the perspective of different tumor cells in detail.

PGC1a in thyroid cancer
The conventional perspective on metabolic changes observed in thyroid carcinomas is that they arise as a consequence of disease progression rather than as instigators themselves (17, 18).However, growing evidence suggests that these metabolic alterations also play regulatory roles in driving cancer progression.Studies have revealed the downregulation of PGC1a expression, particularly in the advanced stages of thyroid cancer (19) and notably in tumors harboring the BRAF V600E mutation (17), which is the most prevalent somatic oncogenic mutation in papillary thyroid carcinoma (20,21).A comprehensive analysis on The Cancer Genome Atlas (TCGA) data from hundreds of patients with papillary thyroid carcinoma underscored the significance of PGC1a downregulation, as it correlated with a higher disease stage and an increased risk of recurrence (17).Multiple mechanisms appear to be involved in suppressing PGC1a expression in TC.The intricate AMPK signaling pathway is implicated in this regulatory process, whereby the activation of protein kinase B (AKT) leads to the suppression of PGC1a expression (17).Further, oxidative metabolism appears to inflict damage upon PGC1a mRNA, consequently dampening its expression (17).This forms a vicious feedforward loop as PGC1a loss exacerbates oxidative stress by curtailing mitochondria and antioxidant responses.Given multifaceted aspects of negative regulation, PGC1a is capable of playing important roles in TC development.Indeed, PGC1a deficiency damages mitochondrial function, elevates oxidative stress, and enhances glycolytic phenotype and disease progression (17).

PGC1a in colorectal cancer
PGC1a is frequently found to be overexpressed in CRC tissues and cell lines.It serves as a key energy mediator, and is induced by aerobic glycolysis (22) and hypoxia (23) in CRC cells.Interestingly, lactate metabolites generated from these processes contribute to the elevation of PGC1a mRNA levels in cancer cells (24,25).Sirtuin3 (SIRT3), a principal mitochondrial deacetylase, has been implicated in modulating PGC1a levels.In metastatic CRC cell lines, the inhibition of SIRT3 using shRNAs has been found to lead to a decrease in both PGC1a mRNA and protein levels (26).Additionally, oncogenic phosphatase PRL3, a regulator of reactive oxygen species (ROS), has been found to exert its influence on upregulated PGC1a expression through the mediation of Rasproximate-1(RAP1) (27).However, in specific scenarios where CRC cells are quiescent, the level of PGC1a has been found to be reduced.For example, linoleic acid was found to induce dormancy in CRC cells by increasing the expression of miR-494, which suppressed energy metabolism genes and maintained cell quiescence through reducing PGC1a levels (28).Interestingly, miR-494 was present at low levels in non-metastatic cases (28).In addition, in normoxic CRC cancer stem cells (CSCs), the expression of hypoxia-inducible factor 1-alpha (HIF-1a) was significantly The expression patterns of PGC1a in diverse cancers.
reduced, leading to the restoration of PGC1a expression in these areas (29).This suggests that HIF1a can act as a negative regulator of PGC1a.Additionally, substances secreted from the tumor microenvironment (TME) may also impact PGC1a expression.For instance, neutrophil elastase (NE), which is released from the neutrophil extracellular traps (NETs) activated toll-like receptor 4 (TLR4) on cancer cells, has been shown to trigger the TLR4/p38/ PGC1a axis, resulting in PGC1a upregulation (30).Notably, PGC1a levels have been found to not only be upregulated in cancer cells but also be heightened in adipose tissues (20), particularly in the context of obesity-related CRC (31) and in cases of cancer cachexia (32).This cachexia-related elevation of PGC1a has been shown to be achieved through the secretion of interleukin-8 (IL-8) in extracellular vesicles (EVs) from CRC cells (32).Cachexia, a late-stage complication of various cancers, is promoted by tumor growth and chemotherapy administration (33).In muscle tissues affected by wasting, abnormal PGC1a expression contributes to mitochondrial dysfunction, which in turn causes cachexia-related symptoms (34).Retrospective studies analyzing clinical tumor samples from patients with CRC have underscored the clinical relevance of PGC1a in CRC (35).Notably, PGC1a expression is positively correlated with nodal metastasis (36), and high tumor PGC1a expression is correlated with reduced overall survival (OS) (36).Hence, PGC1a might serve as a biomarker for assessing CRC invasion and progression.
Functionally, PGC1a plays a crucial role in enhancing mitochondrial biogenesis and oxidative phosphorylation, thereby reprogramming the metabolism to support cell proliferation, growth, and survival (23,30,37).Particularly under hypoxic conditions, PGC1a exerts an antioxidant effect to shield cancer cells from accumulation of ROS (23).Moreover, PGC1a enhances lipid biosynthesis by increasing fatty acid synthase (FASN) levels indirectly through the upregulation of Sp1 and SREBP-1c.This process provides essential building blocks for cell membranes in rapidly proliferating cells (38).Further, PGC1a activates multiple pro-tumorigenic signaling pathways in CRC.It promotes the activation of the AKT/GSK-3b pathway through physical interactions with AKT, although the exact mechanisms remain undefined (39).Additionally, PGC1a boosts leucyl-tRNA synthetase 1 (LARS1) expression, further stimulating AKT/GSK-3b signaling (37).WNT/b-catenin pathway can also be activated by PGC1a, which promotes CRC cell proliferation and inhibits apoptosis (37, 39).PGC1a activates the epithelial-mesenchymal transition (EMT) pathway by upregulating transcription factors like Snail, Slug, and Twist (37, 39), thereby facilitating cancer cell migration and invasion.Recent findings have also indicated that PGC1a can orchestrate lactate oxidation, further promoting the migration and invasion of normoxic CSCs in CRC (29).Additionally, PGC1a can upregulate oxidative phosphorylation and antioxidant genes in chemo resistant cells to adapt to metabolic stress and evade damage from chemotherapeutic agents (23,40).In 5FU-resistant CRC cells, elevated PGC1a expression has been found to be associated with enhanced mitochondrial biogenesis (40), increased expression of BCL2 while simultaneous decreases BAX, cleaved caspase-3, and cleaved PARP-1 (23).Although SIRT1 is not found to regulate PGC1a transcriptionally, it controls deacetylation and activation of PGC1a, thus protecting CRC cells against chemotherapy (41).Suppression of PGC1a restores chemosensitivity in CRC cells (41).Consequently, monitoring changes in PGC1a expression in patient samples during and after treatment can provide insights into tumor response and the progression towards chemoresistance, enabling timely adjustments to alternative treatment regimens before the disease advances.
Above all, PGC1a integrates various oncogenic pathways in CRC, including metabolism, EMT, inflammation, and survival.Targeting PGC1a holds promise as an approach to counter metastasis and improve patient outcomes.Importantly, dietary interventions offer a potential strategy.For instance, linoleic acid (LA) has been shown to induce quiescence in CRC by suppressing PGC1a expression in mice models (28).In vitro studies have demonstrated that manuka honey (MH) reduces colon cancer cell growth in a dose-dependent manner by deactivating PGC1a (42).Clinical trials for CRC are also exploring metabolic drugs such as metformin, which indirectly inhibit PGC1a activity and reprogram metabolism (11,43).Given their favorable safety profiles and ability to target cancer metabolism, these PGC1a-related drugs could offer new treatment avenues for patients with advanced or chemotherapy-refractory CRC.

PGC1a in gastric cancer
Mirroring its expression pattern in CRC, PGC1a has been found to be highly expressed in GC and gastric epithelial cells (44).This elevated expression appears to be influenced by oxidative stress induced by exogenous molecules.Indeed, research has demonstrated that quercetin, a potential prooxidant, increases PGC1a expression under oxidative stress conditions, thereby safeguarding gastric cells from damage (45).Notably, this effect is particularly pronounced after prolonged exposure to H 2 O 2 , whereas quercetin lacks this effect under normal circumstances (45).
Upregulated PGC1a has been found to promote GC progression through the inhibition of cell apoptosis and promotion of EMT (44).A more precise mechanism has now been revealed, wherein PGC1a orchestrates the transcription of SNAI1, subsequently affecting the levels of miR-128b (44).This regulatory cascade, which has been observed both in vitro and in vivo, enhances cell growth and metastasis in GC (44).The influence of posttranscriptional modifications on PGC1a's function is also notable.In GC, PGC1a has been found to undergo phosphorylation by CAB39L-induced p-AMPK, culminating in the regulation of genes associated with mitochondrial respiration complexes (46).Furthermore, PGC1a possesses a pivotal role in the chemoresistance of GC, characterized by disrupted metabolism (47,48).The HCP5/miR-3619-5p axis controls PGC1a expression, subsequently enabling its interaction with CCAAT/enhancer binding protein beta (CEBPB), thereby triggering transcription of carnitine palmitoyltransferase I (CPT1).This in turn enhances fatty acid oxidation (FAO) in GC, ultimately conferring chemoresistance to cancer cells (49).Remarkably, PGC1a suppression could sensitize GC cells to chemotherapeutic agents by inducing metabolic deficiencies and increasing oxidative stress (49).

PGC1a in liver cancer
Liver cancer, also known as hepatocellular carcinoma (HCC), is a major cause of cancer-related mortality worldwide (50).The main risk factors for HCC include chronic hepatitis B and C viral infections, alcohol abuse, nonalcoholic steatohepatitis (NASH), and aflatoxin exposure (51,52).
Emerging evidence suggest that PGC1a is downregulated in HCC tissues and cell lines (2,53).However, the cause of the abnormal expression remains unclear.One proposed mechanism is the accumulation of Parkin-interacting substrate (PARIS) in response to oxidative stress (54), which inhibits PGC1a expression transcriptionally.Additionally, sestrin2 (SESN2), a stress-inducible protein in HCC, has been found to mediate glutamine-dependent activation of PGC1a.SESN2 forms a complex with JNK and FOXO1, enhancing PGC1a transcription.Thus, the reduced SESN2 leads to a decreased PGC1a expression under glucose deprivation (55).The Yes-associated protein 1 (YAP1), a key effector of the Hippo signaling pathway, suppresses PGC1a expression in HCC (56).Moreover, mitochondrial transcription factor B2 (TFB2M), acts as a pivotal oncogene in HCC (57), decreases PGC1a expression at both mRNA and protein level through SIRT3/HIF-1a signaling (58).Interestingly, although hypoxia generally induces PGC1a expression in many diseases (59)(60)(61), HIF-1a has been reported to negatively regulate PGC1a expression (58, 62).However, the precise mechanism underlying this regulation remains unclear, due to a lack of Chip-Seq data and in-depth investigations.
Functional studies have demonstrated that PGC1a inhibits HCC cell proliferation and metastasis.Low PGC1a expression is associated with poor prognosis and aggressive tumor features in HCC patients (2).Mechanistically, PGC1a has been found to counter the Warburg effect, a well-known process promoting cancer progression in HCC cells (63,64).PGC1a achieves this by promoting oxidative phosphorylation (OXPHOS) and inhibiting aerobic glycolysis, partially through PDK1 in a PPARg-dependent manner (2).PGC1a activates PPARg, leading to reduced b-catenin protein levels and inhibition of the WNT/b-catenin pathway and PDK1 expression (2).This results in a decrease in the Warburg effect and tumor suppression.Conversely, impaired PGC1a reverses these effects (2).Moreover, PGC1a regulates gluconeogenic genes with several coactivators, such as hepatic nuclear factor 4 alpha (HNF4a), which has been found to repress pathogenesis of HCC (65).Important targets like G6PC and PCK1, affecting the glycogen accumulation and driving HCC progression (66), are mediated by PGC1a and HNF4a.YAP reduces the ability of PGC1a to coactivate HNF4a at its promoter (56).Post-translational modifications of PGC1a also plays roles in HCC progression.Mitochondrial fission, important in promoting tumor progression in HCC (67,68), reduces NAD + levels and SIRT1 activity, leading to increased acetylation of PGC1a protein.Reduced PGC1a activity has been found to be associated with downregulation of CPT1A and acyl-CoA oxidase 1 (ACOX1) and inhibition of FAO in HCC cells (53), both contributing to HCC growth and metastasis (69,70).Interestingly, general control non-depressible 5 (GCN5) has been found to inhibit PGC1a activity via acetylation ( 16), but the knockout of GCN5 in mouse liver has not been found to have a significant effect on cancer development (71).
However, several studies have proposed an oncogenic function for PGC1a downregulation validations in HCC.For instance, SET8 inhibits Keap1 expression through PGC1a, activating the Nrf2/ ARE pathway and supporting HCC progression (81,82).Interestingly, gankyrin elevates TIGAR level, a well-known regulator of glucose metabolism, via the Nrf2/ARE pathway.This elevation promotesPGC1a nuclear importation, and drives increased glucose metabolism in HCC (83).Therefore, the synergy between Nrf2/ARE activation and nuclear localization of PGC1a could serve as a critical loop in the metabolic changes that support HCC progression.In addition, the phosphoserine aminotransferase 1 (PSAT1)'s interaction with p53 72P variant in HCC cells dissociates PGC1a binding, promotes PGC1a's nuclear translocation (84), mitochondrial transcription factor A (TFAM)mediated OXPHOS and TCA cycle activation (15).Converse effects have been observed for wild-type p53.In HCC, CD147 promotes p53 degradation via the PI3K/AKT pathway (85).Intriguingly, when p53 is exogenously expressed, there is an upregulation of PGC1a levels (86).This suggests that CD147 might impede mitochondrial biogenesis and functionality by suppressing PGC1a/TFAM levels.In this context, PGC1a appears to play a tumor-suppressive role.Thus, targeting PGC1a upstream or downstream pathways is a promising therapeutic strategy for HCC.PPARa agonists that mimic PGC1a re-expression have shown efficacy in HCC models.For example, GW7647 diminishes hepatocarcinogenesis in-humanized mice models (87, 88).

PGC1a in renal cancer
Research has indicated a decline in PGC1a expression in clear cell renal cell carcinoma (ccRCC) tumors compared to normal tissues.This reduction in PGC1a levels aligns with higher tumor grades (89), advanced disease stage (90), worse disease progression, and worse OS (91).One possible reason for this suppression could be the activation of transforming growth factor beta (TGF-b) signaling, which is commonly observed in ccRCC.In fact, when TGF-b signaling is inhibited, PGC1a levels see an increase (92).Moreover, histone deacetylase 1 (HDAC1) and histone deacetylase 7 (HDAC7) have been identified as corepressors, playing a role in suppressing PGC1a via the TGF-b signaling pathway (92).In a related observation, retinoic acid 13 (Stra13 or Dec1) is found to transcriptionally inhibit PGC1a expression.This suggests that Stra13 could be a mediator of HIF-mediated PGC1a suppression during von Hippel-Lindau (VHL) deficiency and hypoxia in ccRCC (90).The actions of Stra13 appear to be closely related to HDAC activity (93).On another front, the epigenetic changes also seem to play a part, particularly through m6A modifications that impacts the stability of PGC1a.A decrease in FTO expression in ccRCC has been linked to a rise in methylated PGC1a mRNA, leading to reduced stability (91).
Functional experiments have uncovered PGC1a's potential as a tumor suppressor in ccRCC.Evidence suggests that reintroducing PGC1a restores the levels of TCA cycle enzymes and mitochondrial functions, reversing the metabolic effects of TGF-b signaling in mice models (92).In addition to inducing oxidative stress, PGC1a sensitizes ccRCC cells to cytotoxic therapies (90).Moreover, PGC1a inhibits cell metastasis in vitro and in vivo by reducing collagen gene expression via miR-29a induction, including collagen type I alpha 1 chain (COL1A1) and collagen type VI alpha 2 chain (COL6A2) (94).Loss of PGC1a in metastatic RCC promotes collagen expression, discoidin domain receptor tyrosine kinase 1 (DDR1) activation, and subsequent snail family transcriptional repressor 1 (SNAIL) stabilization (89).Another tumor suppressor, mitochondrial pyruvate carrier 1 (MPC1), is also regulated by PGC1a (95, 96).PGC1a stimulates the transcription of MPC1 in conjunction with ERR-a and reduced MPC1 negates PGC1a's effects on mitochondrial respiration and biogenesis (95).
However, PGC1a's role seems subtype-dependent.Divergent conclusions have been drawn for the other subtypes.One instance involves the loss of MYBBP1A in 9% of renal tumors (97).MYBBP1A represses PGC1a levels, so the decline of MYBBP1A activates PGC1a directly and indirectly through c-MYB, shifting cellular metabolism from glycolysis to OXPHOS (98).This occurs primarily in the absence of c-MYB or pVHL (97,98).Another scenario involves inactivation of SETD2 in approximately 12% of ccRCC cases (99).SETD2, a histone H3 lysine trimethyltransferase, acts as a ccRCC tumor suppressor (100,101).Loss of SETD2 boosts PGC1a expression and mitochondrial mass in ccRCC (102), prompting a metabolic shift towards oxidative phosphorylation and lipogenesis.In both these contexts, PGC1a takes on a tumorpromoting role in ccRCC.

PGC1a in cholangiocarcinoma
The metabolic reprogramming observed in CCA plays a crucial role in driving its progression (103, 104).CCA cells exhibit increased aerobic glycolysis and glutamine anaplerosis, which allows them to produce essential biosynthetic intermediates vital for their rapid growth and survival (103).Recently, the significance of PGC1a in CCA has been emphasized.Patients with elevated levels of PGC1a expression tend to experience reduced OS and progression-free survival (PFS) and are associated with increased angioinvasion and accelerated recurrence (105).Furthermore, the upregulation of PGC1a drives CCA metastasis by elevating the expression of two critical factors: pyruvate dehydrogenase-alpha 1 (PDHA1) and mitochondrial pyruvate carrier 1 (MPC1) (96).This molecular mechanism reverses the Warburg effect, a hallmark metabolic characteristic often observes in cancer cells.Notably, PGC1a also exerts a significant influence on mitochondrial metabolism regulation and the maintenance of stem-like characteristics in CCA stem cells (105).Therefore, pharmacological interventions involving substances like metformin or SR-18292 have shown promise in inhibiting the effects associated with PGC1a upregulation, mitigating its impact on CCA progression and metastasis (105).

PGC1a in glioblastoma
Emerging evidence underscores the pivotal role of PGC1a in GBM oncogenesis, progression, and treatment resistance.Notably, data from the GBM TCGA and GBM PDX Mayo Clinic databases indicates that GBM exhibits decreased PGC1a mRNA expression compared to normal brain tissue (106).Intriguingly, protein levels of PGC1a have also been reported to be highly expressed in GBM patients, which are located not only in the perinuclear or cytoplasmic regions but also prominently within mitochondria, as proven by publicly available TMAs from US Biomax (107).However, compared to WHO grade IV gliomas, lower-grade gliomas (WHO grade II and III) show increased expression of PGC1a (108).Further survival analysis have indicated that higher PGC1a expression in patients with GBM corresponds to shorter survival times (108), implying that PGC1a loss contributes to gliomagenesis and the transition to glioblastoma.Once a GBM develops, the upregulation of PGC1a within a subset of tumors can promote aggressiveness by driving mitochondrial metabolism.Interestingly, the expression of PGC1a varies in distinct PTEN status; therefore, the protein levels of PGC1a are highest in the SF767 cells (PTEN wildtype) and lowest in the A172 cells (PTENdeleted) (109).
Functional studies demonstrate that PGC1a seems to act as a tumor suppressor in GBM.Aurora kinase A (AURKA) has been implicated in GBM progression and is a potential therapeutic target for this aggressive brain cancer (106, 110).Research has shown that the inhibition of AURKA leads to c-Myc suppression, subsequently resulting in the upregulation of PGC1a, which in turn promotes oxidative metabolism.Furthermore, H3K27ac ChIP-seq and ATACseq show that chromatin accessibility at the potential c-Myc-binding region in the PGC1a promoter is increased, whereas following AURKA inhibition, the binding of c-Myc to the PGC1a promoter is reduced.Concurrently, an enhanced acetylation of the same region in PGC1a promoter has been observed following exposure to AURKA inhibition, indicating that c-Myc may act as a suppressor of PGC1a (106).Moreover, FDA-approved HDAC inhibitors, such as panobinostat, vorinostat, and romidepsin, have been shown to replicate these effects by blocking the Warburg effect in GBM cells.This interference with HDAC1/-2 reduces c-Myc levels while increasing PGC1a expression (111).Another inhibitor, crizotinib, which targets MET kinase (112,113), induces the metabolic reprogramming of GBM cells.This reprogramming, characterized by heightened oxidative phosphorylation and fatty acid oxidation, is also mediated by upregulated PGC1a expression and facilitated by increased CREB phosphorylation after Crizotinib exposure (14,114).The mTORC1 pathway, crucial for cell growth and proliferation in GBM (115), is often activated by epidermal growth factor receptor (EGFR).However, mTORC1 inhibition, accompanied by reduced PGC1a expression, protects GBM cells from hypoxia-induced cell death under the conditions of the TME (116,117).Thus, preclinical experiments have shown that, rapamycin, an mTORC1 inhibitor, triggers adverse effects by promoting cell survival in GBM under hypoxic conditions (116).Concurrently, mTORC1 activation, followed by increased PGC1a expression, sensitizes GBM cells to hypoxia-induced cell death (116).
Similar to other tumors, PGC1a exhibits dual effects in GBM, displaying both anticancer and pro-cancer roles in distinct subtypes.In particular, the fusion of the FGFR3 and TACC3 genes (F3-T3), which act as potent oncogenes, has been identified in approximately 3% of GBM cases (118,119).PGC1a has been shown to be notably overexpressed in F3-T3-positive GBM cells in the presence of PIN4.Elevated PGC1a contributes to mitochondrial biogenesis and respiration through ERRg.Conversely, dampening PGC1a activity hinders the tumor-promoting effects of F3-T3, as demonstrated in both cellular and animal models in GBM (120).

PGC1a in melanoma
Melanoma cells exhibit two distinct transcriptional signatures, proliferative and invasive, which correspond to different cellular phenotypes (121).The metastatic spread of melanoma is thought to involve a transition in cell behavior, shifting from a proliferative program to acquiring migratory and invasive characteristics (122).The expression of PGC1a generally defines these two subsets of melanoma cells (123).In the first subset, PGC1a has been found to be expressed at high levels and plays an important role in melanoma progression and survival.Its upregulation may be triggered by the microphthalmia-associated transcription factor (MITF) via its binding to the upstream regulatory promoter (5,123,124), an event regulated by the Wnt/b-Catenin pathway (125) or an important lipogenic enzyme-ATP-citrate lyase (ACLY) (126).Elevated levels of PGC1a are correlated with poor survival (13,123).In this subset, PGC1a supports melanoma through various mechanisms, with programmed cell death being key.Apoptosis, a process that triggers cell death, is regulated by PGC1a through the regulation of reactive oxygen species (ROS) levels.Thus, suppression of PGC1a leads to a decrease in the expression of genes involved in ROS detoxification, resulting in elevated ROS levels and subsequent induction of apoptosis (123).Ferroptosis, another form of cell death, is involved in melanoma progression and chemoresistance (127).Small molecules that induce ferroptosis, such as RSL3 and ML162, suppress the expression of PGC1a through the Wnt/b-Catenin-MITF pathway.Loss of PGC1a impairs mitochondrial function and antioxidant capacity, leading to excess accumulation of mitochondrial ROS and sensitizing cells to ferroptosis (125).As the activation of the Wnt/b-Catenin pathway in melanoma guides resistance to anti-PD-L1/anti-CTLA-4 treatment (128,129), targeting the Wnt/b-Catenin signaling pathway or PGC1a may improve the effectiveness of immunotherapy by inducing ferroptosis (129).Furthermore, PGC1a tightly interacts with ERRa in melanomas, promoting mitochondrial oxidative metabolism by regulating the expression of genes involved in oxidative phosphorylation and the TCA cycle (13).Depletion or pharmacological inhibition of ERRa selectively inhibits the growth of PGC1a-positive melanomas, but not PGC1a-negative melanomas (13).BAY 1238097, a potent inhibitor of BET binding to histones, strongly represses the expression of PGC1a in melanoma cells, impairing mitochondrial function and inhibiting melanoma cell proliferation (130).These findings support the concept that PGC1a-positive melanomas depend on mitochondrial metabolism for growth.
Conversely, another subpopulation of melanoma cells exhibits lower PGC1a expression, possesses a limited number of mitochondria, and relies heavily on glycolysis to produce energy.This phenotype is often observed in invasive and metastatic melanomas (131,132).In this subset of melanoma cells, PGC1a may be epigenetically silenced through chromatin modifications involving H3K27 trimethylation at its promoter.Pharmacological inhibition of EZH2, an enzyme involved in chromatin modifications, diminishes H3K27me3 markers (133,134), leading to increased PGC1a level and suppression of invasion in PGC1asilenced cells (122).Additionally, BRAF mutation (V600E) suppresses MITF and PGC1a expression in melanoma cells (135).Knocking down PGC1a in these cells promotes a pro-metastatic gene program and enhances metastasis in mice models (131).PGC1a upregulates the expression of inhibitor of DNA binding protein (ID2), which binds and inhibits a diverse array of bHLH transcription factors (136).The binding of ID2 suppresses the transcription factor TCF4, resulting in the suppression of metastasis-related genes including integrins, which are known to affect metastasis (131, 137).Moreover, ID2 suppresses the activity of TCF12, which increases the expression of WNT5A (122).As WNT5A can stabilize YAP protein levels (138, 139), inhibition of TCF12, WNT5A, or YAP blocks melanoma migration and metastasis (122).BRAF inhibitors, such as PLX4032, which have been reported to upregulate PGC1a expression in melanomas (140,141), inhibit metastasis partly by suppressing the Wnt/b-Catenin-MITF pathway and promoting the expression of PGC1a (125).This effect is independent of their cytotoxic or growth-inhibitory properties (131).Kisspeptin-1 (KISS1) functions as a metastasis suppressor by inhibiting metastasis without affecting primary tumor growth (142).In melanoma cells, the transcriptional coactivator PGC1a plays a crucial role in mediating the effects of KISS1 on cell metabolism and metastasis suppression (143).PGC1a helps KISS1 upregulate genes that promote fatty acid oxidation, activates AMPK signaling to inhibit acetyl-CoA carboxylase (ACC), and ultimately shifts cells towards mitochondrial oxidative phosphorylation instead of glycolysis (144).The loss of PGC1a blunts these metabolic changes and abolishes KISS1's antimetastatic effects.The major implication of these bi-signatures is that effective melanoma therapies should target both proliferative and invasive cell types, as they coexist within tumors and can interconvert.Targeting only one phenotype may lead to the selection and outgrowth of alternative phenotypes.Indeed, suppressing of PGC1a-dependent oxidative metabolism activates glycolysis via HIF1a as a compensatory survival mechanism in melanomas.Dual inhibition of PGC1a and HIF1a causes energetic deficits, but partial rescue of melanoma cells have been observed through glutamine utilization (145).Hence, a triple targeting approach involving PGC1a, HIF1a, and glutamine metabolism is necessary to completely block melanoma growth by shutting down oxidative metabolism, glycolysis, and glutaminolysis (145), suggesting that a combination therapy targeting multiple nodes of tumor metabolism is necessary to effectively disrupt energy production and viability, However, overcoming the challenges posed by metabolic heterogeneity and redundancy remains a significant obstacle.

PGC1a in prostate cancer
The expression of PGC1a has generally been found to be reduced in PC, with a further decrease observed in metastatic tissues (146).This downregulation of PGC1a is associated with decreased disease-free survival (DFS) (147)(148)(149).The exact reasons for the downregulation of PGC1a in PC are not fully understood; however, they are believed to be a result of selective pressure during disease progression and metabolic changes.Reports suggest that miRNAs, such as miR-34a-5p, can downregulate PGC1a (150).
It has been reported that PGC1a plays a tumor-suppressor role in the development of PC, inhibiting cancer progression and metastasis (146).Interestingly, some studies have found that the protein level of PGC1a is undetectable in PC cell lines, despite comparable transcript levels to metastatic PC specimens (146,151).The re-expression of PGC1a in vitro and in vivo has been shown to inhibit cell proliferation and cell cycle progression, supporting its antiproliferative activity (146).Moreover, PGC1a suppresses the metastatic properties of PC cells by decreasing integrin signaling, causing cytoskeletal changes (152), and downregulating MYC levels and activity (153).This effect is mediated by its interaction with the transcriptional partner estrogen-related receptor alpha (ERRa).Knockout of ERRa prevents PGC1a from inhibiting invasion, suggesting that the PGC1a/ERRa axis acts as an antagonist to the progression of PC metastasis (146, 152).Furthermore, AMPK, a metabolic regulator in PC, safeguards against cancer progression in mice models (154)(155)(156).Activation of AMPK leads to increased expression of PGC1a and its downstream targets, promoting a switch to a more oxidative and catabolic metabolism and opposing the pro-tumorigenic program of increased lipogenesis (154).However, it has been found that androgens-activated AMPK can increase the expression of PGC1a, promoting mitochondrial content and PC cell growth in cell line models (151).Intriguingly, in a mouse model of benign prostatic hyperplasia, androgen/ testosterone increased prostate size but did not affect PGC1a levels (151).These findings elucidate the complex roles of the AMPK/PGC1a axis in PC development.
In a subpopulation of clinical PC samples, PGC1a level is found to be overexpressed, and PGC1a may therefore exert a tumor supporting role (151,157).In addition to the aforementioned AMPK signaling pathway, another mechanism contributing to the abnormal expression of PGC1a is the loss or mutation of p53 (158).In PC cells with mutated or deleted p53, PGC1a has been found to be expressed at high levels.Overexpression of wild-type p53 in these cells decreases the expression of PGC1a and causes mitochondrial dysfunction (157).However, this regulation axis is highly metabolic-pattern dependence, as p53 suppresses PGC1a level and nuclear localization through redox modification (159).In these settings, the tumor-supporting role of PGC1a is found to depend on the transcription factors (TFs) it partnered with.For example, PPARG activation results in the upregulation of AKT3, which subsequently promotes the nuclear localization of PGC1a.The genes induced by PGC1a promotes mitochondrial biogenesis and energy metabolism, fueling PC progression (160).
In addition, the ETS-related gene (ERG) functions as an oncogenic transcription factor in PC (161).In such cases, PGC1a has been shown to act as a coactivator for ERG, specifically under metabolic stress conditions like glucose deprivation and serum starvation (8).This interaction and coactivation of ERG by PGC1a leads to increased expression of antioxidant genes, such as SOD1 and TXN, which can help clear ROS and benefit PC growth (8).This suggests that PGC1a allows ERG fusion-positive PC cells to adapt and survive under metabolic stress by coactivating the antioxidant transcriptional program of ERG.

PGC1a in ovarian cancer
While PGC1a activity is typically low in normal tissues, several studies have reported frequent overexpression of PGC1a in ovarian tumors compared to that in normal ovaries (162,163).However, it is important to note that the results of the high tumor expression of PGC1a only correlates with tumor differentiation and did not exhibit significant correlations with other clinical features (164).When combined with ERRa, the overexpression of PGC1a reveals a tendency towards increased risk of metastasis and reduced OS (163).Additionally, the expression of both PGC1a and PGC1b has allowed for the classification of ovarian cancer (OC) patients into distinct subgroups.Approximately 25% of studies tumors exhibits high expression of both genes (164), indicating the presence of an overactive mitochondrial gene program.These tumors demonstrates increased mitochondrial content, oxidative metabolism, and OXPHOS (164).Mechanistic studies have shed light on how the aberrant activation of PGC1a contributes to OC progression and therapeutic resistance.Recent studies have identified PGC1a as a critical driver of OC progression, particularly in high-grade serous OC (HGSOC), which exhibits metabolic heterogeneity (165)(166)(167).In OC, the high-OXPHOS state has been linked to chronic oxidative stress (165).This stress leads to the increased aggregation of PML nuclear bodies, which subsequently activates PGC1a through deacetylation.As a result, PGC1a induces the expression of electron transport chain (ETC) components, enhancing mitochondrial respiration in high-OXPHOS cancer cells.Knockdown of PGC1a reduces both ETC gene expression and oxygen consumption rate in these cells (165).Furthermore, PGC1a plays a pivotal role in mediating the response to conventional chemotherapies.PGC1a has been found to be a key regulator of reactive ROS production (165), which are crucial determinants of the apoptotic response to cisplatin in OC cells (168).Elevated expression or activity of PGC1a is correlated with enhanced chemosensitivity by promoting mitochondrial oxidative metabolism and respiration (165).Conversely, reducing PGC1a activity and levels decreases sensitivity to chemotherapy in OC.

PGC1a in nasopharyngeal carcinoma
There is increasing evidence that metabolic reprogramming driven by PGC1a promotes NPC progression and resistance to treatment.PGC1a has been found to be upregulated in NPC and its high expression has been associated with shorter OS after radiation therapy (169).PGC1a contributes to NPC cell survival by activating FAO pathways, which provide cells with ATP and the antioxidant NADPH.These metabolic alterations allow NPC cells to adapt and thrive under challenging conditions.PGC1a works in conjunction with the transcription factor CEBPB to enhance the expression of CPT1A, a gene involved in FAO, thereby sustaining this metabolic reprogramming (169).Consequently, these changes confer radioresistance to NPC cells (169).Furthermore, TGFb1, a signaling molecule, can upregulate PGC1a and activate FAO to facilitate EMT and invasion of NPC cells.Specifically, TGFb1 stimulates phosphorylation and expression of AMPKa1 (170), which, in turn, phosphorylates and activates PGC1a in NPC.This activation leads to transcriptional upregulation of FAOrelated genes (170).Inhibiting PGC1a expression and components of the FAO pathway have been shown to reduce EMT, invasion, and metastasis of NPC both in vitro and in vivo.

PGC1a in breast cancer
Overall, PGC1a expression has been found to be reduced in breast tumor tissues compared to that in the normal breast epithelium (171,172).This downregulation of PGC1a potentially facilitates the Warburg effect, in which cells increase their dependence on glycolysis and glucose uptake, while decreasing mitochondrial oxidative phosphorylation, even when oxygen is available (173).Such metabolic shifts enhance the proliferation and survival of cancer cells.A key mechanism that drives this shift is the regulation of mitochondrial deacetylase SIRT3 (171,174).Although the exact cause of PGC1a's downregulation in BC cells is yet to be fully elucidated, certain epigenetic modifications such as negative regulation by miR-485 and miR-217 have been proposed (175,176).Interestingly, despite its general downregulation in breast tumors, the expression of PGC1a varies according to tumor subtypes and their metastatic tendencies.Specifically, HER2 + and triple-negative breast tumors (TNBT) express high levels of PGC1a (177, 178).Moreover, elevated expression of PGC1a has been detected in BC cells that predominantly metastasize to the lungs or bone, as opposed to the liver and brain (179).Similarly, circulating tumor cells (CTCs) released from BC in mice models and patients exhibit elevated PGC1a expression (180).Indeed, PGC1a knockdown in a metastatic cell line has been found to result in reduced CTC numbers and metastasis, whereas overexpression of PGC1a has been found to increase lung metastasis in vivo (179,180).Interestingly, BC cells with low PGC1a levels possess increased metastatic ability when overexpressing PGC1a levels (180).It is worth noting that inhibiting mitochondrial respiration with biguanides in such cells is not found to mitigate PGC1a-induced metastasis (179), suggesting that the augmented metastatic phenotype is not simply attributed to the PGC1a-induced escalation in oxidative phosphorylation.Instead, PGC1a increases overall bioenergetic capacity and flexibility to facilitate metastasis, allowing cancer cells to cope with energy disruptors (179).In these conditions, the induced PGC1a ensures the metabolic demands of aggressive breast tumors.
Early research has also highlighted PGC1a's involvement in the initiation of BC (181).In particular, its interaction with EglN2, an enzyme involved in the regulation of the hypoxia-inducible factor (HIF) pathway, appears to be central to the modulation of mitochondrial function and has been implicated in BC tumorigenesis (182,183).In both normoxic and hypoxia conditions, EglN2 forms a complex with both PGC1a and NRF1, leading to the induction of FDXR.This maintains mitochondrial function and contributes to breast tumorigenesis in an HIFindependent manner (182).Importantly, in the absence of PGC1a, the effects of EglN2 overexpression on BC cells are blocked.
Furthermore, PGC1a's metabolic regulatory functions in BC often operate in collaboration with other transcription factors like ERRa or p53.For instance, the interplay between PGC1a and ERRa governs a spectrum of metabolic genes (172), driving increased mitochondrial respiration, ATP production, and other processes that culminate in heightened tumor aggression and drug resistance in BC (177, 184, 185).In ERBB2 + cancer cells, PGC1a positively regulates glutamine metabolism in conjunction with ERRa (177).This regulation contributes to increased glutamine uptake, increased flux through the citric acid cycle (CAC), and enhanced lipogenesis from glutamine, particularly under hypoxic conditions (177).The AMPK orchestrates this energy-sensor axis of PGC1a/ERRa (186).When AMPK is activated, PGC1a/ERRa represses folate cycle and one-carbon metabolism, which are vital for sustaining cell growth in cancer cells.Consequently, repression increases the sensitivity to anti-folate therapy (186).It is well established that mutant p53 confers pro-tumorigenic functions in BCs.Notably, as a key downstream of p53, its function is differentially controlled by the codon 72 variant, highlighting the importance of PGC1a as a "gain-of-function" partner of mutant p53 (187).
From a therapeutic point of view, early studies have hinted at the potential benefits of targeting PGC1a in BC treatment.For instance, interventions with vascular endothelial growth factor receptor 2 (VEGFR2) blockade or the AMPK signaling activator, 5-aminoimidazole-4-carboxamide riboside (AICAR), have shown promising shifts in mitochondrial biogenesis and cancer cell behaviors by modulating PGC1a.One study shows that VEGFR2 blockade by Ki8751 leads to increased activity of PGC1a and thereby stimulates the expression of TFAM, which is essential for mitochondrial DNA transcription and replication (188).
Subsequent metabolic reprogramming contributes to increased ROS production and apoptosis in BC cells treated with Ki8751 (188).Moreover, AICAR increases PGC1a expression in triplenegative BC (TNBC) cells (189), mediating mitochondrial biogenesis and contributing to a reduced pro-tumor phenotype and increased chemosensitivity (189).Compound 11, a novel inverse agonist targeting ERRa (190), disrupts ERRa binding to its coactivator PGC1a, with promising anti-tumor activity against triple-negative BC cells and tumors (190).The use of polyethylene glycol-modified graphene oxide (PEG-GO) also results in the selective suppression of PGC1a in cancer cells (191).The reduced ATP production impairs the assembly of the F-actin cytoskeleton and formation of lamellipodia, consequently inhibiting the migration and invasion of metastatic BC cells (191).Importantly, the induction of PGC1a guides drug resistance in the course of chemotherapy of BC (5).Endocrine-resistant BC cells have shown higher PGC1a expression than the parental sensitive lines.PGC1a sensitizes BC cells to low estrogen levels during estrogen deprivation therapy (192)(193)(194).This may be an early adaptive response to endocrine therapy that potentially contributes to the development of chemoresistance over time by allowing estrogen hypersensitivity (192).Therefore, inhibiting PGC1a with SR-18292 prevents the growth of therapy resistant cell lines in a dosedependent manner, while re-expression of PGC1a increases the viability of resistant cells when treating with certain endocrine therapies, such as tamoxifen, fulvestrant, palbociclib, or aromatase inhibitors (193).

Implications of PGC1a in the tumor microenvironment
The tumor microenvironment (TME) is a complex and dynamic landscape where cancer cells interact with, including immune cells, fibroblasts, and the extracellular matrix.The role of PGC1a in the TME is pivotal yet underexplored.Its involvement goes beyond mere energy metabolism, extending to modulating immune responses and influencing tumor progression and therapy resistance.
Significant insights have been gathered from studies on T cells.Naive T cells normally have high levels of PGC1a, which support their metabolic demands for proliferation and effector functions through mitochondrial biogenesis and oxidative metabolism.However, during T-cell activation, PGC1a expression is progressively repressed (195,196).Notably, one study observes that, although the mRNA expression of PGC1a in memory CD8 + T cells decreases upon activation, its protein expression increases (197).This suggests that specific posttranslational mechanisms may regulate the stability of PGC1a in CD8 + T cells.In melanomas, tumor-infiltrating T cells have shown a loss of PGC1a level due to the chronic AKT signal activation (195).Additionally, exhausted T cells, experiencing continuous stimulation and hypoxia increase expression of Blimp-1, which further suppress PGC1a expression (196).This impairs their adaptive metabolic responses to hypoxia via mitochondrial biogenesis.Of note, overexpressing PGC1a in these cells enhances their persistence and recall responses, particularly improving the central memory T cell formation and sustained metabolic fitness upon re-exposure to infections (197).Interestingly, the co-stimulatory molecule 4-1BB, which is abundantly expressed in exhausted T cells, promotes mitochondrial biogenesis, fusion, and respiratory capacity (198)(199)(200).Costimulation with 4-1BB elevates PGC1a levels, mediating the metabolic effects of 4-1BB signaling (199).Without PGC1a, 4-1BB agonists are less effective at enhancing mitochondrial function and improving anti-tumor responses, or enhance adoptive T cell therapy (199).Thus, restoring the PGC1a expression in functional T cells could offer a strategy to reprogram metabolism in tumor-infiltrating T cells and boost their anti-tumor activity.
Research also shows that PPARg is essential for maturation of alternatively activated macrophages, enabling monocytes to differentiate into M2 macrophages (201,202).Indeed, the expression of PGC1a is elevated in these macrophages (203).In breast cancer, a reduced level of miR-382 maintains PGC1a expression in tumor-associated macrophages (203), facilitating the induction of the M2 type through the PPARg signaling pathway.Fibroblasts also respond to regulation by PGC1a.A recent study found that knocking down PGC1a in normal human lung fibroblasts reduces mitochondrial mass and function (204).This alteration increases activation of matrix synthetic fibroblasts along with secretion of soluble profibrotic factors (204).In mouse models, the loss of PGC1a in induced mouse embryonic fibroblasts (iMEFs) leads to a more aggressive and metastatic melanoma phenotype (205).Similarly, lower PGC1a expression in cancer-associated fibroblasts (CAFs) of oral squamous cell carcinoma (OSCC) enhances the proangiogenic phenotype of CAFs through the PGC1a/PFKFB3 axis (206).Moreover, PGC1a impacts mesenchymal stromal cells (MSCs) (207).In melanoma, cancer cells attract MSCs to the tumor site and induce mitochondrial biogenesis by upregulating PGC1a (207).Furthermore, PGC1a controls mitochondrial transfer from MSCs to melanoma cells, thereby supporting melanoma growth (207).

Discussion
PGC1a is rapidly establishing itself as an indispensable regulator of cancer cell metabolism across numerous malignancies.In cancers, multiple mechanisms are involved in the abnormal expression of PGC1a, particularly in the transcriptional regulation.Therefore, based on the current research progress, we have summarized the relevant findings (Figure 2).
Although the expression and functions of PGC1a are contextdependent, it primarily serves as a pivotal orchestrator of mitochondrial biogenesis, oxidative metabolism, antioxidant defenses, and other cellular processes.When PGC1a expression is downregulated, the Warburg effect is facilitated, leading to disease advancement.Subsequent metabolic aberrations can be rectified by reinstating PGC1a levels.This may halt cell proliferation and invasion, and make cells more receptive to chemotherapy.In contrast, PGC1a upregulation promotes oxidative phosphorylation, allows cancer cells to adapt to stress, and promotes a more aggressive cancer phenotype.This duality in biological behavior shows PGC1a's adaptability in aligning with various co-regulators and executing functions tailored to its environment.Thus, to target PGC1a effectively, understanding its nuanced role in each cancer subtype is indispensable.
Central to PGC1a's operations is its position at the crossroads of several pivotal signaling pathways involved in cancer.It processes signals from the Wnt/b-catenin, TGF-b, AMPK, AKT, and p53 pathways to regulate downstream metabolic activities.By partnering with transcription factors like ERRa, NRF1, and YAP, PGC1a can drive specific changes in gene expression.Moreover, post-translational modifications such as phosphorylation and acetylation offer another layer of control over its activity.Decoding these intricate molecular ties is a critical step in comprehending PGC1a's multifaceted functions and how they may go awry in cancer.An intriguing development is the increasing evidence of PGC1a's profound effect on the tumor microenvironment, particularly its interaction with immune cells.
Strategic targeting of PGC1a in cancer therapy, therefore, requires a nuanced approach that considers its dual functionality.In cases where PGC1a functions as a tumor suppressor, its upregulation or enhanced activity can shift cancer cell metabolism away from the Warburg effect.This metabolic shift involves reducing glycolysis and increasing oxidative phosphorylation, which typically slows cancer progression and may make cancer cells more amenable to interventions that induce metabolic stress.Enhancing PGC1a's expression could be achieved through gene therapy techniques, and small molecule activators.Conversely, in cancers where PGC1a contributes to a more aggressive phenotype, its function is linked to enhanced oxidative phosphorylation, supporting cancer cell adaptation to metabolic and oxidative stress.In such cases, inhibiting PGC1a might reduce the cancer cells' ability to sustain high energy demands and resist hostile environments, such as those imposed by chemotherapy.This can be approached through the use of small molecule inhibitors that disrupt PGC1a's interaction with its coactivators or transcription factors it regulates.Additionally, RNA interference technologies could selectively knock down PGC1a mRNA, diminishing its protein levels and thus its functionality in cancer cells.Both strategies-enhancing or inhibiting PGC1a-must consider the cancer type, the specific metabolic profile of the tumor, and the systemic implications of altering metabolic pathways.For instance, enhancing oxidative metabolism in non-tumor cells might also affect normal cells, leading to unintended consequences like increased reactive oxygen species.Similarly, inhibiting PGC1a in aggressive tumors must be carefully managed to avoid crippling normal cells' ability to manage oxidative stress.Effective therapeutic strategies should aim to disrupt this metabolic adaptability by targeting PGC1a along with its regulatory network to block compensatory pathways that facilitate resistance to therapy.Furthermore, PGC1a's impact on the tumor microenvironment, particularly through its influence on the metabolic states of T cells and macrophages, is gaining attention.By modulating immune cell metabolism, PGC1a could potentially alter the immunological landscape of tumors, reducing immune suppression and enhancing the efficacy of immunotherapies.This understanding suggests that strategies which leverage PGC1a's role in the tumor microenvironment could complement direct targeting approaches, creating a multifaceted attack on tumor growth.
In summary, PGC1a's multifaceted roles in cancer metabolism indicate that it is a promising therapeutic target for cancer.Developing drugs that can specifically modulate PGC1a's activity, tailored to the unique metabolic profiles of different cancer types, represents a promising approach in oncology.By doing these, we are now on the brink of translating our understanding of this metabolic mediator into its clinical benefits against cancer.

FIGURE 2
FIGURE 2Schematic overview of transcriptional regulation of PGC1a in cancers.
was supported by Nanjing Medical Science and technique Development Foundation (Grant No. QRX17105).lymphocyte-induced maturation protein-1ERRgEstrogen related receptor gamma.