CELF Family Proteins in Cancer: Highlights on the RNA-Binding Protein/Noncoding RNA Regulatory Axis

Abstract

Post-transcriptional modifications to coding and non-coding RNAs are unquestionably a pivotal way in which human mRNA and protein diversity can influence the different phases of a transcript’s life cycle. CELF (CUGBP Elav-like family) proteins are RBPs (RNA-binding proteins) with pleiotropic capabilities in RNA processing. Their responsibilities extend from alternative splicing and transcript editing in the nucleus to mRNA stability, and translation into the cytoplasm. In this way, CELF family members have been connected to global alterations in cancer proliferation and invasion, leading to their identification as potential tumor suppressors or even oncogenes. Notably, genetic variants, alternative splicing, phosphorylation, acetylation, subcellular distribution, competition with other RBPs, and ultimately lncRNAs, miRNAs, and circRNAs all impact CELF regulation. Discoveries have emerged about the control of CELF functions, particularly via noncoding RNAs, and CELF proteins have been identified as competing, antagonizing, and regulating agents of noncoding RNA biogenesis. On the other hand, CELFs are an intriguing example through which to broaden our understanding of the RBP/noncoding RNA regulatory axis. Balancing these complex pathways in cancer is undeniably pivotal and deserves further research. This review outlines some mechanisms of CELF protein regulation and their functional consequences in cancer physiology.

CircARID1A binds to IGF2BP3 in gastric cancer and promotes cancer proliferation by forming a circARID1A-IGF2BP3-SLC7A5 RNA–protein ternary complex

“…RNA-binding proteins (RBPs) are essential players in RNA metabolism and regulate RNA splicing, transport, surveillance, decay and translation [5]. RBPs also participate in tumorigenesis and progression and are potential targets for tumor therapy [6][7][8]. The insulin like growth factor II mRNA binding protein 3 (IGF2BP3) is a mammalian IGF2 mRNA-binding protein family member and contains 2 RNA recognition motifs (RRM) in its N-terminus and 4 hnRNPK homology (KH) domains at the C-terminus.…”

Dysregulation of CELF4 Splicing Factor in Pancreatic Neuroendocrine Tumors Enhances Aggressiveness and Alters Mtor Pathway and Everolimus Response

“…These ndings on CELF4 are completely original, as only a marginal nding of unexplored signi cance has identi ed a methylation-related expression of this gene in PanNETs (24). Actually, while the role of CELF4 in alternative splicing and neurological pathophysiology is well established (20,(22)(23)(24)(25), its precise implication in cancer is still poorly understood. In colorectal cancer, bioinformatic analysis of open databases suggested a prognostic role involving an intronic variant (26), reviewed in (21), while, in endometrial cancer, CELF4 expression seems to be downregulated due to hypermethylation and may also provide prognostic information (28).…”

“…In this scenario, in the course of pilot studies the splicing factor CELF4 stood out due to its notable dysregulation. CELF4 (CUGBP ELAV-like family member 4) is one of the 6 members of the CELF family of RNA binding proteins associated with regulation of pre-RNA alternative splicing (20). Earlier studies on CELF4 expression were con icting, suggesting either a broad tissue expression or more restricted to nervous tissue (21), while reports on gene mutations and variants in humans and experimental studies on rodents associated this gene to neurological, neurodevelopmental, and behavioral defects (22)(23)(24)(25).…”

Deciphering the Complex Molecular Pathogenesis of Myotonic Dystrophy Type 1 through Omics Studies

“…CELF1 and 2 are highly expressed in various tissues, such as skeletal muscle, brain, and heart, constituting the first and most studied group. CELF3-6 are mostly present in neurons, and CELF6 can also be found in kidneys and testes [17,18].…”