Key Takeaways & Executive Findings
- •• • PCBP2 posttranscriptional modifications drive breast cancer progression via upregulation of UFD1 and NT5E, as demonstrated in Mol Cancer Res 2021;19:86–98. This identifies PCBP2 as a candidate therapeutic target for breast cancer subtypes resistant to standard chemotherapy. • • PABPN1 regulates mRNA alternative polyadenylation to inhibit bladder cancer progression (Cell Biosci 2023;13:45). Loss of PABPN1 function correlates with aggressive bladder cancer phenotypes, suggesting its utility as a prognostic biomarker and potential target for polyadenylation-directed therapy. • • IGF2BP3 promotes acquired resistance to EGFR inhibitors in non-small cell lung cancer through metabolic reprogramming (Cancer Res 2023;83:2187–2207). This establishes IGF2BP3 as a driver of tyrosine kinase inhibitor failure, with direct implications for combination strategies in EGFR-mutant NSCLC. • • LARP1 functions as a post-transcriptional regulator of survival and tumorigenesis in ovarian cancer (Nucleic Acids Res 2016;44:1227–1246). Targeting LARP1-mediated translation may overcome chemoresistance in ovarian cancer, where current platinum-based regimens face high recurrence rates.
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Abstract
RNA-binding proteins (RBPs) constitute a family of over 2000 proteins that regulate post-transcriptional gene expression through interactions with target transcripts. These interactions govern alternative splicing, cleavage and polyadenylation, RNA localization, translation, N6-methyladenosine (m6A) modification, and DNA double-strand break repair. RBPs are frequently dysregulated in cancers, where they modulate oncogene expression, invasion, metastasis, and apoptosis inhibition. This review examines recent advances in understanding RNA-binding domains (RBDs) and the RNA processes they regulate in tumorigenesis. We summarize the roles of six well-characterized RBDs in cancers and the molecular mechanisms by which RBPs contribute to chemotherapy resistance. Specific examples include PCBP2-mediated upregulation of UFD1 and NT5E in breast cancer, PABPN1 regulation of mRNA alternative polyadenylation in bladder cancer, and IGF2BP3-driven metabolic reprogramming conferring resistance to EGFR inhibitors in non-small cell lung cancer. We discuss the potential of targeting RBPs for cancer therapy and review RBPs that are dysregulated across malignancies. Additionally, we highlight recently developed tools for predicting RBP-RNA binding activities, including molecular dynamics simulation, nuclear magnetic resonance, and crystallography. These computational and structural approaches provide valuable support for ongoing research efforts to elucidate the mechanisms by which RBDs recognize RNA motifs, a process mediated by van der Waals interactions and hydrogen bonds. The clinical implications of RBP dysregulation underscore their prognostic significance and therapeutic potential as emerging targets in oncology.
1. Introduction
Current cancer therapies face substantial clinical friction from drug resistance and incomplete understanding of post-transcriptional regulatory mechanisms. While targeted therapies against kinases and immune checkpoints have improved outcomes, resistance frequently emerges through adaptive changes in RNA metabolism. RNA-binding proteins (RBPs) represent a largely untapped class of therapeutic targets, yet their selective RNA recognition mechanisms remain poorly defined, hindering rational drug design. Existing approaches have stalled due to the lack of high-resolution structural data on RBP-RNA interfaces and the absence of predictive tools for binding specificity.
This review addresses these bottlenecks by consolidating recent advances in RNA-binding domain (RBD) structural biology and RBP-mediated oncogenic processes. We integrate findings from molecular dynamics simulations, nuclear magnetic resonance, and crystallography to elucidate how van der Waals interactions and hydrogen bonds mediate RBD-RNA recognition. By systematically analyzing RBPs such as PCBP2, PABPN1, IGF2BP3, and LARP1 across multiple cancers, we provide a framework for targeting RBPs to overcome chemotherapy resistance. The review also highlights emerging computational tools for predicting RBP-RNA binding activities, offering a pathway to accelerate the development of RBP-directed therapeutics.
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XU Zemei, CUI Yukun (2025). The dual role of RNA-binding proteins: promotion of tumorigenesis, drug resistance, and emerging therapeutic targets. Acta Biochimica et Biophysica Sinica. https://doi.org/10.3724/abbs.2025099
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Frequently Asked Questions
What specific molecular mechanisms drive IGF2BP3-mediated resistance to EGFR inhibitors in non-small cell lung cancer?
IGF2BP3 promotes acquired resistance to EGFR inhibitors through metabolic reprogramming, as shown in Cancer Res 2023;83:2187–2207. This involves IGF2BP3-dependent stabilization of mRNAs encoding metabolic enzymes, shifting cancer cell metabolism to bypass EGFR blockade. The exact pathways include enhanced glycolysis and glutaminolysis, but the study identifies IGF2BP3 as a key upstream regulator. Targeting IGF2BP3 in combination with EGFR inhibitors may delay or reverse resistance.
How does PABPN1 regulate alternative polyadenylation to inhibit bladder cancer progression, and what are the quantitative effects?
PABPN1 regulates mRNA alternative polyadenylation, and its downregulation correlates with bladder cancer progression (Cell Biosci 2023;13:45). Mechanistically, PABPN1 controls the length of 3′ untranslated regions, affecting mRNA stability and translation. Loss of PABPN1 leads to shortened 3′UTRs in oncogenes, increasing their expression. The study demonstrates that PABPN1 overexpression inhibits cell proliferation and invasion, but specific fold-changes are not provided in the abstract. Clinically, PABPN1 levels may serve as a prognostic marker.
What structural techniques have been most effective in elucidating RBD-RNA recognition, and what are their limitations?
Molecular dynamics (MD) simulation, nuclear magnetic resonance (NMR), and crystallography are employed to elucidate RBD-RNA recognition mechanisms. NMR provides dynamic information in solution but is limited by protein size. Crystallography yields high-resolution static structures but may not capture conformational flexibility. MD simulations complement these by modeling interactions over time, but require accurate force fields. The review notes that van der Waals interactions and hydrogen bonds are crucial, yet the specific recognition code remains unresolved, limiting structure-based drug design.
What is the clinical potential of targeting LARP1 in ovarian cancer, and what are the expected challenges?
LARP1 is a post-transcriptional regulator of survival and tumorigenesis in ovarian cancer (Nucleic Acids Res 2016;44:1227–1246). Targeting LARP1 could disrupt translation of mRNAs involved in cell survival, potentially overcoming platinum resistance. However, challenges include the lack of small-molecule inhibitors with sufficient specificity, as LARP1 shares domains with other RBPs. Additionally, systemic inhibition may affect normal tissues given LARP1's role in general translation. Further preclinical studies are needed to establish therapeutic window and efficacy in resistant ovarian cancer models.
How do RBPs contribute to DNA double-strand break repair, and what are the implications for chemotherapy resistance?
RBPs regulate DNA double-strand break repair by interacting with transcripts encoding repair proteins. For example, PD-L1 competes with the RNA exosome to regulate the DNA damage response, and can be targeted to sensitize to radiation or chemotherapy (Mol Cell 2019;74:1215–1226.e4). This indicates that RBPs can modulate repair capacity, leading to resistance to DNA-damaging agents. Targeting such RBPs could restore chemosensitivity. The review highlights that RBPs are involved in multiple repair pathways, but specific quantitative effects on repair efficiency and drug sensitivity vary by context.
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