RNA-binding protein MEX3A controls G1/S transition via regulating the RB/E2F pathway in clear cell renal cell carcinoma

MEX3A is an RNA-binding protein that mediates mRNA decay through binding to 30 untranslated regions. However, its role and mechanism in clear cell renal cell carcinoma remain unknown. In this study, we found that MEX3A expression was transcriptionally activated by ETS1 and upregulated in clear cell renal cell carcinoma. Silencing MEX3A markedly reduced clear cell renal cell carcinoma cell proliferation in vitro and in vivo. Inhibiting MEX3A induced G1/S cell-cycle arrest. Gene set enrichment analysis revealed that E2F targets are the central downstream pathways of MEX3A. To identify MEX3A targets, systematic screening using enhanced cross-linking and immunoprecipitation sequencing, and RNA-immunoprecipitation sequencing assays were performed. A network of 4,000 genes was identified as potential targets of MEX3A. Gene ontology analysis of upregulation of the cell proliferation pathway was highly enriched. Further assays indicated that MEX3A bound to the CDKN2B 30 untranslated region, promoting its mRNA degradation. This leads to decreased levels of CDKN2B and an uncontrolled cell cycle in clear cell renal cell carcinoma, which was confirmed by rescue experiments. Our findings carcinoma.

Automated summary

MEX3A is an RNA-binding protein that promotes mRNA decay through binding to 30 untranslated regions. This study reveals that MEX3A is upregulated in clear cell renal cell carcinoma and its transcription is activated by ETS1. Silencing MEX3A reduces cell proliferation and induces G1/S cell-cycle arrest. Gene set enrichment analysis identified E2F targets as the central downstream pathways of MEX3A. Further assays demonstrated that MEX3A binds to the CDKN2B 30 untranslated region, promoting its mRNA degradation and leading to uncontrolled cell cycle in clear cell renal cell carcinoma.