RBMX suppresses tumorigenicity and progression of bladder cancer by interacting with the hnRNP A1 protein to regulate PKM alternative splicing

Abstract

The prognosis for patients with metastatic bladder cancer (BCa) is poor, and it is not improved by current treatments. RNA-binding motif protein X-linked (RBMX) are involved in the regulation of the malignant progression of various tumors. However, the role of RBMX in BCa tumorigenicity and progression remains unclear. In this study, we found that RBMX was significantly downregulated in BCa tissues, especially in muscle-invasive BCa tissues. RBMX expression was negatively correlated with tumor stage, histological grade and poor patient prognosis. Functional assays demonstrated that RBMX inhibited BCa cell proliferation, colony formation, migration, and invasion in vitro and suppressed tumor growth and metastasis in vivo. Mechanistic investigations revealed that hnRNP A1 was an RBMX-binding protein. RBMX competitively inhibited the combination of the RGG motif in hnRNP A1 and the sequences flanking PKM exon 9, leading to the formation of lower PKM2 and higher PKM1 levels, which attenuated the tumorigenicity and progression of BCa. Moreover, RBMX inhibited aerobic glycolysis through hnRNP A1-dependent PKM alternative splicing and counteracted the PKM2 overexpression-induced aggressive phenotype of the BCa cells. In conclusion, our findings indicate that RBMX suppresses BCa tumorigenicity and progression via an hnRNP A1-mediated PKM alternative splicing mechanism. RBMX may serve as a novel prognostic biomarker for clinical intervention in BCa.

Comprehensive Analysis of Co-Mutations Identifies Cooperating Mechanisms of Tumorigenesis

“…Genes of this family have been frequently associated with cancers [ 19 , 20 , 21 ]. RBMX is a chromosome-x-linked RNA binding motif protein, which has also been associated with bladder cancer [ 22 ] and kidney cancer [ 23 ]. A good example for altered miRNA-matching 3′-UTR binding sequences is the TP53 mutation (C→T) at chromosome 17 position 7,673,780, which altered the binding sequence to miR-150-5p in TCGA’s LGG cohort.…”

The Dispensable Roles of X-Linked Ubl4a and Its Autosomal Counterpart Ubl4b in Spermatogenesis Represent a New Evolutionary Type of X-Derived Retrogenes

“…This is supported by different mechanisms including alternative splicing, polyadenylation and apoptosis in somatic and germ cells, and the obvious examples of genes are hnRNPG-T, CSTF2T, and BIRC8 (Elliott et al, 2000;Richter et al, 2001;Dass et al, 2002;Grozdanov et al, 2018;Bousoik et al, 2019;Zhou et al, 2019;Yan et al, 2021). RBMX protein has been implicated in splice site selection, and RBMX-derived retrogene product, hnRNPG-T, could be specialized in alternative splicing in germ cells (Elliott et al, 2000;Zhou et al, 2019;Yan et al, 2021). CSTF2T could function in the non-canonical polyadenylation of mRNAs in germ cells (Dass et al, 2002;Grozdanov et al, 2018).…”

Current Development and Application of Anaerobic Glycolytic Enzymes in Urothelial Cancer

“…Yan et al reported that RNA-binding motif protein X-linked (RBMX) regulated cell proliferation, colony formation, and metastatic ability in metastatic BC [ 106 ]. They observed that RBMX competitively inhibited the combination of the RGG motif in hnRNP A1 and the sequence flanking PKM exon 9, leading to the formation of lower PKM2 and higher PKM1 levels, which attenuated the tumorigenicity and progression of metastatic BC.…”