RBM25 Drives Hepatocellular Carcinoma Progression by Stabilizing YAP Through Regulating Oncogenic Splicing‐switch of MYPT1

Deregulated alternative splicing (AS) is a hallmark of hepatocellular carcinoma (HCC), yet the specific splicing factors driving oncogenic programs remain largely uncharacterized. Here, we identify RNA-binding motif protein 25 (RBM25) as a potent oncogenic driver that is overexpressed in HCC and correlates with dismal patient prognosis. Functionally, RBM25 depletion impairs HCC progression across in vitro models, in vivo xenografts, and patient-derived organoids. Integrated transcriptomic and interactome profiling reveals that RBM25 orchestrates a specific AS landscape, most notably promoting exon 13 inclusion of MYPT1. Mechanistically, RBM25 recruits PRPF40A to facilitate the production of the oncogenic MYPT1-L isoform. This isoform switch acts as a molecular stabilizer for the transcriptional co-activator YAP, thereby sustaining Hippo pathway dysregulation and tumor growth. Finally, a high-throughput screen of the US drug collection identified candicidin as a small-molecule inhibitor that suppresses RBM25 expression, effectively phenocopying RBM25 knockdown. Our findings define the RBM25-MYPT1-YAP axis as a critical vulnerability in HCC and nominate RBM25 as a viable prognostic biomarker and therapeutic target.

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Publication Details

Journal
Advanced Science
Published
2026-09-16
DOI
https://doi.org/10.1002/advs.77792
Primary Topic
Hippo pathway signaling and YAP/TAZ
Type
article
Field-Weighted Citation Impact
0.00

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article

RBM25 Drives Hepatocellular Carcinoma Progression by Stabilizing YAP Through Regulating Oncogenic Splicing‐switch of MYPT1

Baofeng Zhao, Yangfan Qi, Lili Zhi, Tian Huang et al.
Advanced Science
Hippo pathway signaling and YAP/TAZ
article

RBM25 Drives Hepatocellular Carcinoma Progression by Stabilizing YAP Through Regulating Oncogenic Splicing‐switch of MYPT1

Baofeng Zhao, Yangfan Qi, Lili Zhi, Tian Huang, Yang Wang, Ge Zhang, Rong Liu, Wenjing Zhang, Dan Chen, Huanhuan Wei, Jinrui Zhang, Chaoqun Chen, Lingya Feng, Lei Chen, Xiaolong Liu
article en

Abstract

Deregulated alternative splicing (AS) is a hallmark of hepatocellular carcinoma (HCC), yet the specific splicing factors driving oncogenic programs remain largely uncharacterized. Here, we identify RNA-binding motif protein 25 (RBM25) as a potent oncogenic driver that is overexpressed in HCC and correlates with dismal patient prognosis. Functionally, RBM25 depletion impairs HCC progression across in vitro models, in vivo xenografts, and patient-derived organoids. Integrated transcriptomic and interactome profiling reveals that RBM25 orchestrates a specific AS landscape, most notably promoting exon 13 inclusion of MYPT1. Mechanistically, RBM25 recruits PRPF40A to facilitate the production of the oncogenic MYPT1-L isoform. This isoform switch acts as a molecular stabilizer for the transcriptional co-activator YAP, thereby sustaining Hippo pathway dysregulation and tumor growth. Finally, a high-throughput screen of the US drug collection identified candicidin as a small-molecule inhibitor that suppresses RBM25 expression, effectively phenocopying RBM25 knockdown. Our findings define the RBM25-MYPT1-YAP axis as a critical vulnerability in HCC and nominate RBM25 as a viable prognostic biomarker and therapeutic target.

Advanced Science
Dalian Institute of Chemical Physics (CN), Dalian Medical University (CN), Peking University (CN), Sir Run Run Shaw Hospital (CN), Soochow University (CN), Peking University Cancer Hospital (CN), Shanghai Institute of Nutrition and Health (CN), Second Affiliated Hospital of Dalian Medical University (CN), Peking University First Hospital (CN), First Affiliated Hospital of Dalian Medical University (CN), Zhejiang University (CN)
National Natural Science Foundation of China, Department of Education of Liaoning Province, Department of Science and Technology of Liaoning Province
Openalex Percentile: Top 14%
Hippo pathway signaling and YAP/TAZ
DOIOpen Access PDFOpenAlex
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