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

Abstract

MEX3A is an RNA-binding protein that mediates mRNA decay through binding to 3′ 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 upregulated genes bound by MEX3A indicated that negative regulation of the cell proliferation pathway was highly enriched. Further assays indicated that MEX3A bound to the CDKN2B 3′ 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 revealed that MEX3A acts as a post-transcriptional regulator of abnormal cell-cycle progression in clear cell renal cell carcinoma.

A transcriptional network required for bradyzoite development in Toxoplasma gondii is dispensable for recrudescent disease

“…While this number may appear to be quite large (this represents ~1/10 th of the T. gondii transcriptome), RNA binding proteins in other systems have been shown to have similar broad mRNA interaction profiles. These include ELAVL1 60 , the CCCH zinc finger domain containing PRRC2B 61 and MEX3A 62 , all of which have hundreds to thousands of putative mRNA targets.…”

Systematic analysis of RNA-binding proteins identifies targetable therapeutic vulnerabilities in osteosarcoma

“…MEX3A is elevated in all the OS and the GCTB, whereas AKAP1 is most highly elevated in the two aggressive OS, and then in the GCTB, but not in the less aggressive OS. Using three orthogonal datasets for the mRNA targets of these three RBPs (an intersection of CLIPseq targets and downregulated transcripts upon shRNA-mediated knockdown of IGF2BP3 52 (Supplementary Data 8 ), RIPseq targets of MEX3A 53 and eCLIPseq targets of AKAP1 from the ENCODE database ( https://www.encodeproject.org/genes/8165/ )), we interrogated the expression levels of their targets in the transcriptomes of the OS and GCTB cells. In case of IGF2BP3, we find the highest number of upregulated target transcripts in the two aggressive OS, I063_021 and OSRH_2011/5 and in OSKG (Supplementary Fig.…”

“…The transcriptomic, eCLIPseq and RIPseq datasets used to generate Supplementary Fig. 8 and Supplementary Data 8 are publicly available as supplementary data in Palanichamy et al 52 , Qiu et al 53 . and in the ENCODE database ( https://www.encodeproject.org/genes/8165/ ).…”

Machine-learning based integrating bulk and single-cell RNA sequencing reveals the SLC38A5-CCL5 signaling as a promising target for clear cell renal cell carcinoma treatment

“…Deciphering the communication network showed the remarkably activated regulons ETS1 and MEF2C. ETS1 is involved in cancer progression and linked to decreased survival in most malignancies including breast cancer [46] , gastric carcinoma [47] , and ccRCC [48] . For MEF2C, the dual roles depend on cancer types.…”