Downregulated RNA-binding motif protein 5 (RBM5) promotes the development and progression of various tumors, including bladder cancer (BC). Alternative splicing (AS) plays a crucial role in the progression of cancer by producing protein isomers with different functions or by promoting nonsense-mediated mRNA decay (NMD). However, whether RBM5 modulates the progression of BC through AS-NMD remains unexplored. In this study, we revealed that the downregulation of RBM5 expression promoted the expression of coactivator-associated arginine methyltransferase 1 (CARM1) in BC cells and tissues. Increased expression of CARM1 facilitated the activation of the Wnt/β-catenin axis and cell proliferation, which then contributed to the poor prognosis of patients with BC. Interestingly, RBM5 bound directly to CARM1 mRNA and participated in AS-NMD, downregulating the expression of CARM1. In addition, we revealed that protein kinase catalytic subunit alpha (PRKACA) functioned as a phosphorylated kinase of GSK3β, was regulated by CARM1 at the transcription level, and promoted the growth and progression of BC cells. Furthermore, in this study, we demonstrated a regulatory mechanism of Wnt/β-catenin activation through the RBM5/CARM1/PRKACA axis and identified a novel potential target for treating BC.
下调的RNA结合基序蛋白5（RBM5）可促进包括膀胱癌（BC）在内的多种肿瘤的发生发展。选择性剪接（AS）通过产生具有不同功能的蛋白质异构体或促进无义介导的mRNA降解（NMD），在癌症进展中发挥关键作用。然而，RBM5是否通过AS-NMD调控膀胱癌进展尚不明确。本研究揭示，RBM5表达下调可促进膀胱癌细胞及组织中辅激活因子相关精氨酸甲基转移酶1（CARM1）的表达。CARM1表达增加能促进Wnt/β-catenin信号轴激活和细胞增殖，进而导致膀胱癌患者不良预后。值得注意的是，RBM5可直接结合CARM1 mRNA并参与AS-NMD过程，从而下调CARM1表达。此外，本研究还发现蛋白激酶催化亚基α（PRKACA）作为GSK3β的磷酸化激酶，在转录水平受CARM1调控，并能促进膀胱癌细胞生长与进展。本研究进一步阐明了通过RBM5/CARM1/PRKACA轴激活Wnt/β-catenin信号的调控机制，为膀胱癌治疗提供了新的潜在靶点。
肿瘤(癌症)患者之家