The dual role of RNA-binding proteins: promotion of tumorigenesis, drug resistance, and emerging therapeutic targets

Abstract

Cancer is a complex and multifaceted disease characterized by a multitude of molecular factors. RNA-binding proteins (RBPs) have emerged as pivotal regulators of tumor development, progression, and chemoresistance through their interactions with target transcripts. These interactions regulate a multitude of processes, including alternative splicing, cleavage and polyadenylation, RNA localization, translation, N6-methyladenosine (m6A) RNA modification, and DNA double-strand break repair. The RBP family comprises over 2000 proteins and plays a critical role in oncogene expression, invasion, metastasis, and inhibition of apoptosis. However, the mechanisms by which RBPs selectively recognize RNAs remain an active area of research. In this review, we examine recent advancements in understanding RNA-binding domains and the RNA processes regulated by RBPs in tumorigenesis, summarize and highlight the roles of RNA-binding domains in cancers and the molecular mechanisms of RBPs in chemotherapy resistance, discuss the potential of targeting RBPs for cancer therapy and review RBPs that are dysregulated in cancers. Additionally, we highlight recently developed tools for predicting RBP-RNA binding activities to provide valuable support for ongoing research efforts.

1. Introduction

RNA-binding proteins (RBPs) play crucial roles in the tumorigenesis and progression of cancers by regulating mRNA metabolism. Additionally, certain RBPs are involved in RNA modifications, specifically N6-methyladenosine (m6A) modifications, exemplified by IGF2BPs. Furthermore, they modulate the expression and activity of m6A readers such as Musashi 1 (MSI1) [1]. RBP-RNA binding occurs at coding sequences, 5′ untranslated regions (5′UTRs), and 3′ untranslated regions (3′UTRs). This interaction is mediated by specific RNA-binding domains (RBDs) that recognize and bind to particular RNA motifs [2]. RBDs have been the subject of research for several decades. However, the specific mechanisms by which RBDs recognize RNA motifs remain an active area of investigation. Previous studies have demonstrated that van der Waals interactions and hydrogen bonds play crucial roles in this recognition process [3]. A variety of techniques, including molecular dynamics (MD) simulation, nuclear magnetic resonance (NMR), and crystallography, have been employed to elucidate the mechanisms by which RBDs recognize their target RNAs.

The majority of RBPs are upregulated in colorectal cancer (CRC) compared with normal tissues. RBPs play pivotal roles in the regulation of posttranscriptional gene expression, and dysregulation of RBP-RNA interactions can have detrimental effects on cancer progression [4,5]. Therefore, an increasing number of studies have investigated the relationship between RBPs and cancer.

In this review, we provide an overview of the structural and functional characteristics of six well-characterized RBDs involved in RNA recognition, and summarize the roles of RBPs in oncology, aiming to elaborate on the mechanisms through which RBPs contribute to tumorigenesis and chemotherapy resistance in diverse cancers. Additionally, we provide insights into their prognostic significance and clinical therapeutic potential.