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- Title
Downregulated RBM5 Enhances CARM1 Expression and Activates the PRKACA/GSK3β Signaling Pathway through Alternative Splicing-Coupled Nonsense-Mediated Decay.
- Authors
Zhang, Yanping; Li, Fang; Han, Zhenwei; Teng, Zhihai; Jin, Chenggen; Yuan, Hao; Zhang, Sihao; Sun, Kexin; Wang, Yaxuan
- Abstract
Simple Summary: Previous studies have demonstrated that downregulated RBM5 promotes the progression of bladder cancer. Alternative splicing (AS) plays a crucial role in the progression of cancer by promoting nonsense-mediated mRNA decay (NMD). However, whether RBM5 modulates the progression of BC through AS-NMD remains unexplored. The present study revealed that RBM5 negatively regulates the expression of CARM1 by binding directly to its mRNA and participating in the NMD process of CARM1 mRNA in BC cells. CARM1 mediates the activation of Wnt/β-catenin and RBM5 by promoting the phosphorylation of GSK3β. Protein kinase catalytic subunit alpha (PRKACA) acts as a phosphorylated kinase of GSK3β and is regulated by CARM1 at the transcription level. The results proved that there exists a regulatory mechanism for Wnt/β-catenin activation through the RBM5/CARM1/PRKACA axis and identified a new potential target for treating BC. 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.
- Subjects
BLADDER tumors; PROTEIN kinases; MICRORNA; ARGININE; DNA methyltransferases; T-test (Statistics); RESEARCH funding; DESCRIPTIVE statistics
- Publication
Cancers, 2024, Vol 16, Issue 1, p139
- ISSN
2072-6694
- Publication type
Article
- DOI
10.3390/cancers16010139