Glucose transporters (GLUTs) are a family of transmembrane protein that regulate the entry of extracellular glucose into cells during the processes of glucose metabolism (39). There are many subtypes of GLUTs, of which GLUT4, GLUT3, GLUT2, and GLUT1 are mostly relevant to the glucose metabolism. Insulin-regulated GLUT4 membrane transport is the most important glucose transporter in adipocytes and skeletal muscle cells (40). GLUT3 is a kind of glucose transporter mainly distributed in nerve tissue (41). GLUT2 is critical for the maintenance of hepatocytes' glucose balance and meanwhile plays a key role in the glucose perception of the nervous system (42). GLUT1 is a kind of glucose transporter that is widely distributed in many tissues and organs (43). It regulates basal glucose uptake during maintenance of normal physiological functions of most cells. This may be closely related to the rapid growth of tumor cells requiring a large amount of glucose. The expression and dysfunction of GLUTs are related to many diseases, especially in the metabolism of tumor cells (44). For example, the deficiency of lncRNA HAND2-AS1 is identified to up-regulate GLUT1 and GLUT3 in the process of promoting glucose uptake in osteosarcoma (19) (Figure 1 and Table 1).

In pathological conditions, impaired membrane transport or functions of certain GLUTs are an important cause of disorders of glucose levels in various tumor cells, such as hepatocellular carcinoma (HCC) cells (45, 48), renal tumor cells (64), osteosarcoma cells (65), and so on. The high expression of GLUTs satisfies the energy needs of tumor cells. In a recent study, a new lncRNA named lnc-p23154 was found to promote glucose uptake and glycolysis by GLUT1, and it affected oral squamous cell carcinoma metastasis and invasion. A further study demonstrated that lnc-p23154 inhibited the transcription of miR-378a-3p by interacting with the promoter of miR-378a-3p. MiR-378a-3p could then bind to the 3′UTR of GLUT1 directly and repressed GLUT1 expression both at the mRNA and at the protein level (46). In non-small-cell lung cancer (NSCLC), the lncRNA-NEF is down-regulated, comparing adjacent healthy tissues and tumor tissues in patients with NSCLC. The overexpression of lncRNA-NEF inhibits NSCLC cell proliferation and glucose uptake and down-regulated GLUT1 expression. In short, lncRNA-NEF targets GLUT1 to influence the proliferation of NSCLC cells (47). The relationship between glucose uptake and HOTAIR has also been revealed in HCC cells. HOTAIR mediates the expression of GLUT1 via activating mammalian target of rapamycin (mTOR) signaling, which may provide a therapeutic strategy for HCC (48) (Figure 1 and Table 1).

Besides influencing the expression of GLUT1, lncRNAs are also likely to affect the distribution of GLUT1 in tumor cells to regulate the uptake of glucose. In gastric cancer cells, the expression of GLUT1 surrounding the cell membrane is induced by MACC1-AS1, which is a lncRNA, that is highly expressed under metabolic pressure. This is an indication that MACC1-AS1 is likely to promote glucose uptake and then promote glycolysis by increasing the distribution of GLUT1 in the vicinity of the cell membrane. However, the specific relationship between the MACC1-AS1 and GLUT1 remains to be further studied (49). The above results indicate that the role of lncRNAs in glycolysis-mediated proliferation or metastasis of tumor cells depends on GLUTs (Figure 1 and Table 1).

As we all know, the cells absorb glucose in the cytoplasm and catalyze the formation of pyruvate through a series of key enzymes of glucose metabolism. The process by which pyruvate enters the mitochondria to produce large amounts of energy is called mitochondrial oxidative phosphorylation, while the process in which pyruvate is oxidized directly in the cytoplasm to produce lactic acid that does not enter the mitochondria is called glycolysis. Glycolysis and mitochondrial oxidative phosphorylation are inseparable. The process of glycolysis and mitochondrial oxidative phosphorylation involve a large number of enzymes, of which the major ones include hexokinases (HKs) (66), pyruvate kinase enzyme M (PKM) (67), lactate dehydrogenase (LDH) (68), citrate synthase (CS), and so on. Alterations of lncRNAs drive tumor cells to aerobic glycolysis and mitochondrial oxidative phosphorylation through regulation of metabolic enzymes involving these pathways. In HCC progression, lncRNA Ftx affects glucose metabolism reprogramming through the PPARγ pathway. On the one hand, it promotes glycolysis by promoting the expression and activity of phosphofructokinase (PFK) and LDH, and at the same time weakens the activity and expression of tricarboxylic acid cycle key enzymes CS, isocitrate dehydrogenase (IDH), and α-ketoglutarate dehydrogenase (OGDH) (45). The lncRNA SNHG3 is likely to play a similar role. Li et al. found that SNHG3 could up-regulate the expression of the metabolic enzymes PFK, PKM, CS, IDH, and OGDH to regulate the energy metabolism of ovarian cancer through mitochondrial proteomics analysis (50) (Figure 1 and Table 1).

HKs catalyzes the first and irreversible step of glycolysis (69). Hexokinase 1 (HK1) is one of the subtypes of HK. A cytoplasmic lncRNA LINC00470 involving fused in sarcoma (Fus), AKT, and HK1 pathway promotes glycolysis in glioblastoma cells by repressing HK1 ubiquitination (51). In addition to HK1, there are three other enzymes of HK identified, out of which hexokinase 2 (HK2) is the major enzyme that is closely involved in tumor cell glycolysis (70). For example, lncRNA taurine up-regulated gene 1 (TUG1) is disclosed to be related to HK2 involved in glycolytic metabolism and cell metastasis in HCC. The process involves a series of cascades, including TUG1/p21/miR-455-3p/AMPKβ2/HK2/Snail (52). TUG1 has also been associated with the HK2-mediating glycolysis regulating the viability ability of osteosarcoma cells, although the exact mechanism is unknown (53). In addition, one of the main functions of lncRNAs is to interact with microRNAs acting as a molecular sponge. It has been reported that lncRNA Pvt1, which is usually regarded as an oncogene, influences the expression of HK2, promoting glycolysis, and tumor progression in osteosarcoma and gallbladder cancer through acting as a competitive endogenous RNA to directly bind to miR-497 or miR-143, respectively (54, 55). Similarly, HOTAIR binding to miR-125 and miR-143 directly promotes the expression HK2 in esophageal squamous cell carcinoma cells (56). The above research findings fully show that HK2 is implicated in the regulation of tumor progression and metabolic programs involving lncRNAs (Figure 1 and Table 1).

PFKFB3 and PKM2 are also key enzymes regulating glycolysis and oxidative phosphorylation. LncRNA YIYA regulates the PFKFB3 phosphorylation in cyclin-dependent kinase 6-dependent pathway, promoting glycolysis in breast cancer cell (57). The overexpression of lncRNA FEZF1-AS1 in colorectal cancer cells reduced the ubiquitination degradation of PKM2. As a result, the expression of cytoplasmic and nuclear PKM2 protein in glucose metabolism process increased (58). Contrary to FEZF1-AS1, LINC01554 shows a suppressive function because of the acceleration in PKM2 ubiquitination degradation in HCC cells (59) (Figure 1 and Table 1).

LDHA catalyzes the last step of aerobic glycolysis, which is highly critical to the glycolysis phenotype of tumor cells (71). Overexpression of LDHA promotes tumor cell malignant transformation and growth, indicating the important role of LDHA in tumor initiation or maintenance (68). In lung cancer cell lines, it is reported that lncRNA CRYBG3 regulates glycolysis rather than oxidative phosphorylation to increase lung cancer cell proliferation through interacting with LDHA. Knockdown of lncRNA CRYBG3 reduces the expression and activity of LDHA and then decreases the consumption of glucose and pyruvate; however, there are no notable changes in the level of oxidative phosphorylation including all kinds of tricarboxylic acid cycle intermediates regardless of overexpression or knockdown lncRNA CRYBG3 (60). In bladder cancer, the lncRNA cancer susceptibility candidate 8 (CASC8) is reported to function as a tumor suppressor and reduces glycolysis via inhibiting fibroblast growth factor receptor 1-mediated LDHA phosphorylation at Tyr10 (61) (Figure 1 and Table 1).

The PPP is another way of catabolizing glucose, which can produce large amounts of NADPH, providing a reducing agent for various synthesis reactions of tumor cells. The ribose-5-phosphate (R5P) produced by this pathway can also provide raw materials for the synthesis of many substances (72). Glucose-6-phosphate dehydrogenase (G6PD) is the first key enzyme in the oxidation phase of the PPP, which transfers glucose-6-phosphate to 6-phosphogluconate. G6PD is up-regulated in many tumor cells and tumor tissues and generally its level correlates with the overall survival of patients. The lncRNA protein disulfide isomerase family A member 3 pseudogene 1 (PDIA3P) is a 2099-bp lncRNA located at chromosome 1q21.1. It has been reported that PDIA3P regulates multiple myeloma growth and drug resistance through up-regulating G6PD in the PPP. Researchers further discovered that PDIA3P increased the G6PD expression and the PPP flux through enhancing c-MYC transactivation activity bound to the G6PD promoter (62). Similar to PDIA3P, the lncRNA prostate cancer gene expression marker 1 (PCGEM1) also affects pentose phosphate shunt to facilitate biosynthesis of nucleotide and generates NADPH for redox homeostasis as a coactivator for c-MYC and androgen receptor (63). Although the PPP is not the main pathway of glucose metabolism and there are not many studies on lncRNAs and PPP, it is reasonable to believe that PPP is also an important link in the regulation of lncRNAs during tumor progression (Figure 1 and Table 1).

Lipid synthesis is a landmark change in tumor cells. Synthesis of lipid can not only provide a large number of membrane phospholipids as raw materials for the continuous division and proliferation of tumor cells, but also synthesize a series of cancer-promoting lipid signaling molecules, such as phosphatidylinositol and sphingomyelin, etc.

FASN is a key rate-limiting enzyme catalyzing de novo fatty acid biogenesis (85). Since FASN was discovered, its role in tumor growth and intracellular signal transduction has been widely studied. HAGLR, also called HOXD-AS1, is generally elevated in NSCLC and it is regarded as a predictor of poor patient survival. The proliferation and invasion ability of NSCLC cells decreased after HAGLR knockdown and cells mainly remained in the G1 phase. Furthermore, the expression of FASN and the amount of free fatty acids significantly reduced with the decrease of HAGLR expression in the non-small cells (78). In human nasopharyngeal carcinoma cells, high expression of HOTAIR is positively correlated with FASN expression. Adenovirus encoded short hairpin RNA knockdown of HOTAIR causes the decrease of free fatty acid and FASN at transcriptional and post-transcriptional levels in nasopharyngeal carcinoma cells (79). Although the specific mechanism, of how lncRNAs regulate lipid synthesis involving FASN is unclear, they at least partly demonstrate that lncRNAs play an important role in tumor cells by FASN-mediated lipid synthesis. In osteosarcoma cells, lncRNA Pvt1 was found to act as a sponge molecule to adsorb miR-195. As a result, the expression of FASN, B-cell lymphoma 2 protein, and Cyclin D1 increased. At the same time, the study also showed that silencing Pvt1 reduced cell invasion, and FASN could reverse this effect (80). Sterol regulatory element binding protein 1 (SREBP1) is a major transcription factor involved in lipid accumulation and desaturation. Zhang et al. in their study indicated that the lncRNA LINC01138 increased the arginine methylation of SREBP1 at the post-transcriptional level to regulate lipid desaturation and cells growth of clear cell renal cell carcinoma by interacting with protein arginine methyltransferase 5 (77) (Figure 2 and Table 2).

Fat mobilization is the first step in lipid catabolism, and adipose triglyceride lipase (ATGL) is a first key lipase that has been discovered in recent years to initiate fat mobilization (86, 87). It is vital to maintain the balance of lipid storage mobilization (88). In fact, ATGL has been reported to be reduced in leiomyosarcoma, non-small cell lung cancer as well as pancreatic adenocarcinoma, and the levels of ATGL are associated with patients survival (89). In the diet-induced murine HCC model of steatohepatitis and human HCC, the expression of ATGL is also found to be decreased by Di Leo (90). Although it is frequently reported that ATGL shows anti-neoplastic effect, some studies have proposed its tumor-promoting function (91). Interestingly, Liu et al. found that the expression of ATGL at transcriptional level and post-transcriptional level is higher in human HCC tissues and orthotopic HCC mouse model, which is exactly the opposite of Di Leo. It is showed that high expression of ATGL promoted the growth of HCC cells by catalyzing the production of diacylglycerol (DAG) and free fatty acids (FFA). This opposite phenomenon may be due to differences in the clinicopathological features of the patients and the mouse model. Simultaneously, the study also indicated that the lncRNA NEAT1 could regulate the expression of ATGL and affect the abnormal lipidosis of HCC cells through ATGL. Further research confirmed miR-124-3p/ATGL/DAG+FFA to participate in the regulation effect of NEAT1 on the lipid decomposition in HCC and thus promoted the progress of HCC (92) (Figure 2 and Table 2).

It is well-known that the most important form of fatty acid decomposition is β-oxidation of fatty acids (FAO), and studies have shown that lncRNAs are also extremely important in the oxidation of fatty acids. Acyl-CoA synthetase (ACS) is the rate-limiting enzyme in the first step of the fatty acid oxidation reaction. HULC is the first lncRNA identified to be specifically elevated in HCC compared with normal liver tissues (93). Cui et al. revealed that, in hepatoma carcinoma cells, HULC could modulate lipogenesis by the pathway involving miR-9, peroxisome proliferator-activated receptor alpha (PPARA), and ACS long-chain family members 1 (ACSL1), and interestingly, ACSL1 also seems to have a positive feedback effect on HULC expression during this process (81). In gastric cancer cells, transforming growth factor β1 secreted by mesenchymal stem cells could promote the high expression of lncRNA MACC1-AS1. The high expression of MACC1-AS1 relieved the inhibitory effect of miR-145-5p on FAO by inhibiting miR-145-5p, ultimately promoting the stemness and chemoresistance depending on FAO of gastric cancer cells (94). Taken together, lncRNAs participate in lipid decomposition in different ways to affect tumor progress (Figure 2 and Table 2).

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.