The interplay between RNA-binding proteins (RBPs) and coding/non-coding RNAs creates an intricate network of connections that significantly impact cell physiology with consequences in cancer (–). Integrative proteo-transcriptomic analyses indicate the existence of dynamic RBP-RNA interactions only partially deciphered and involved in immunomodulatory effects (), cell signaling (), viability (), metabolic reprogramming (, ), or secretory pathways (). The relevance of these interactions also emerges when better investigating the mechanism of action of drugs with anti-inflammatory/anti-cancer activities, remarkably including the post-transcriptional regulation to exert their pleiotropic effects (–). Deciphering and prioritizing these interaction dynamics offer a tremendous opportunity to interfere with new mechanisms that could lead to novel synergistic, durable treatments for cancer.
In this Research Topic, we collected five articles as examples describing the post-transcriptional activity of a natural compound, the pathological functions of selected miRNAs and their interplay with long non-coding RNAs (lncRNAs), and the emerging prognostic significance of selected RBPs and lncRNAs in solid tumors.
Chen et al. characterized the Glaucocalyxin A (GLA)-induced anti-proliferative activities on ovarian cancer cells. This natural compound, deriving from Rabdosia japonica, was already known for anti-cancer and anti-inflammatory properties (). The authors reported drug-induced cell phenotypes associated with high-mobility group box 3 (HMGB3) downregulation. They found that GLA concomitantly induces the expression of miR-374b-5p, matching complementarity with a specific region on HMGB3 3’UTR, significantly reducing HMGB3 protein expression and identifying a functional axis sustained by HMGB3 mRNA and miR-374b-5p interaction. This report adds new details about the mechanism of action of GLA, including a relevant post-transcriptional control strongly associated with the drug’s anti-cancer effects.
Lin et al. addressed soft-tissue sarcoma (STS). Although representing less than 1% of all human cancers, STS severely impacts cancer mortality due to the absence of therapies to tackle advanced disease stages. The authors interrogated The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) databases and compared STS with healthy tissues, identifying more than three hundred differentially expressed RBPs. Notably, nine out of those were found to predict patients’ 1-year, 3-year, and 5-year survival rates. These data could open new mechanistic studies on critical RBPs that could represent new therapeutic targets and/or improve the diagnosis and stratification of patients with soft-tissue sarcoma.
In the research article by Yuan et al., selected lncRNAs are presented as mediators of cuproptosis in hepatocellular carcinoma (HCC). With a similar approach using TCGA dataset on liver hepatocellular carcinoma and comparing normal versus tumor samples, the authors identified a signature of differentially expressed copper death-related lncRNAs with potential prognostic significance. Among ten copper death- and 22 copper metabolism-related targets, four lncRNAs, namely AL590705.3, LINC02870, KDM4A-AS1, and MKLN1-AS were validated using in vitro HCC cellular models supporting post-transcriptional mechanisms in cuproptosis pathways.
Li et al. identified an interplay between the lncRNA LBX2-AS1 and the microRNA mir-597-3p in osteosarcoma. The authors found this lncRNA as one of five targets composing a signature predicting tumor survival. Given its indicated role as an oncogene in several tumor types, the authors investigated the effects of LBX2-AS1 knockdown in osteosarcoma, detecting an increase in apoptosis and less severe phenotypes in vivo. By exploring potential miRNA targets as regulators of LBX2-AS1, the authors identified mir-597-3p as a potential sponged molecule, pointing out BRD4 as a target of this microRNA. Notably, they found an implication of the LBX2-AS1/mir-597-3p/BRD4 axis in the resistance to the JQ-1 BET bromodomain inhibitor, reporting that LBX2-AS1 silencing shifts the JQ-1 IC50 in osteosarcoma cells.
In the published review, Budi et al. summarize the latest knowledge on the roles of miR-128 in multiple cancer types. In particular, the authors discuss the physiological and pathological functions of miR-128, its biogenesis and molecular targets. The review contains details on the role of miR-128 in multiple malignancies such as breast cancer, lung cancer, thyroid cancer, head and neck cancer, osteosarcoma, glioma, leukemia, and multiple myeloma. The authors also discuss the role of miR-128 in the development of chemoresistance with implications for immunotherapy, offering a point of view on mechanisms underlying the progression and drug resistance of cancer cells potentially associated with a dysregulation of miR-128.
Several RNA-binding proteins and domains show preferred or flexible affinity towards a specific RNA consensus. The fate of recognized coding or non-coding RNAs depends on the competition between different RBPs that can “read the multiple codes” carried by single RNA substrates, forming dynamic post-transcriptional networks. This issue emphasizes the need to quantitatively unravel competitive interactions of RBPs and RNAs, including the characterization of RNA-binding sites, to expand our repertoire of disease biomarkers, therapeutic targets and druggability strategies, and elucidate mechanisms and versatility of anti-cancer drugs.
Statements
Author contributions
VGD conceived and discussed the Research Topic. All the authors contributed to managing the published articles and reviewing them. All the authors contributed to the editorial manuscript writing and revision.
Funding
VGD is supported by Fondazione Cassa di Risparmio Trento e Rovereto and by Italian Ministry of Health (GR-2016-02361552, GR-2019-12369266).
Conflict of interest
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.
Publisher’s note
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.
References
1
MooreMJ. From birth to death: the complex lives of eukaryotic mRNAs. Science (2005) 309:1514–8. doi: 10.1126/science.1111443
2
NagSGoswamiBDas MandalSRayPS. Cooperation and competition by RNA-binding proteins in cancer. Semin Cancer Biol (2022) 86:286–97. doi: 10.1016/j.semcancer.2022.02.023
3
DassiE. Handshakes and fights: the regulatory interplay of RNA-binding proteins. Front Mol Biosci (2017) 4:67. doi: 10.3389/fmolb.2017.00067
4
LoneSNBhatAAWaniNAKaredathTHashemSNisarSet al. miRNAs as novel immunoregulators in cancer. Semin Cell Dev Biol (2022) 124:3–14. doi: 10.1016/j.semcdb.2021.04.013
5
BudakotiMPanwarASMolpaDSinghRKBüsselbergDMishraAPet al. Micro-RNA: the darkhorse of cancer. Cell Signal (2021) 83:109995. doi: 10.1016/j.cellsig.2021.109995
6
MirzaeiSZarrabiAAsnafSEHashemiFZabolianAHushmandiKet al. The role of microRNA-338-3p in cancer: growth, invasion, chemoresistance, and mediators. Life Sci (2021) 268:119005. doi: 10.1016/j.lfs.2020.119005
7
LiuCLiHChuFZhouXXieRWeiQet al. Long non−coding RNAs: key regulators involved in metabolic reprogramming in cancer (Review). Oncol Rep (2021) 45. doi: 10.3892/or.2021.8005
8
ThongonNCastiglioniIZucalCLatorreED’AgostinoVBauerIet al. The GSK3β inhibitor BIS I reverts YAP-dependent EMT signature in PDAC cell lines by decreasing SMADs expression level. Oncotarget (2016) 7. doi: 10.18632/oncotarget.8437
9
FabbianoFCorsiJGurrieriETrevisanCNotarangeloMD’AgostinoVG. RNA Packaging into extracellular vesicles: an orchestra of RNA-binding proteins? J Extracell Vesicles (2020) 10. doi: 10.1002/jev2.12043
10
BlagdenSPWillisAE. The biological and therapeutic relevance of mRNA translation in cancer. Nat Rev Clin Oncol (2011) 8:280–91. doi: 10.1038/nrclinonc.2011.16
11
RossbachM. Small non-coding RNAs as novel therapeutics. Curr Mol Med (2010) 10:361–8. doi: 10.2174/156652410791317048
12
NeilCRSeilerMWReynoldsDJSmithJJVaillancourtFHSmithPGet al. Reprogramming RNA processing: an emerging therapeutic landscape. Trends Pharmacol Sci (2022) 43:437–54. doi: 10.1016/j.tips.2022.02.011
13
D’AgostinoVGSighelDZucalCBonomoIMicaelliMLolliGet al. Screening approaches for targeting ribonucleoprotein complexes: a new dimension for drug discovery. SLAS Discovery Adv Life Sci R D (2019) 24:314–31. doi: 10.1177/2472555218818065
14
XiangZWuXLiuXJinY. Glaucocalyxin a: a review. Nat Prod Res (2014) 28:2221–36. doi: 10.1080/14786419.2014.934235
Summary
Keywords
RNA, RNA-binding proteins, post-transcriptional control, drug, mechanism of action (MOA), anti-cancer, anti-inflammatory
Citation
Salvati E, Lewinska A, Dassi E, Wnuk M and D’Agostino VG (2023) Editorial: RNA recognition landscapes and anticancer drug targeting. Front. Oncol. 13:1222883. doi: 10.3389/fonc.2023.1222883
Received
15 May 2023
Accepted
30 May 2023
Published
19 June 2023
Volume
13 - 2023
Edited and reviewed by
Olivier Feron, Université catholique de Louvain, Belgium
Updates
Copyright
© 2023 Salvati, Lewinska, Dassi, Wnuk and D’Agostino.
This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Vito G. D’Agostino, vito.dagostino@unitn.it
Disclaimer
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.