RNA binding protein RALY activates the cholesterol synthesis pathway through an MTA1 splicing switch in hepatocellular carcinoma.

Abstract

Alternative splicing is an important RNA processing event that contributes to RNA complexity and protein diversity in cancer. Accumulating evidence demonstrates the essential roles of some alternatively spliced genes in carcinogenesis. However, the potential roles of alternatively spliced genes in hepatocellular carcinoma (HCC) are still largely unknown. Here we showed that the HnRNP Associated with Lethal Yellow Protein Homolog (RALY) gene is upregulated and associated with poor outcomes in HCC patients. RALY acts as a tumor-promoting factor by cooperating with splicing factor 3b subunit 3 (SF3B3) and modulating the splicing switch of Metastasis Associated 1 (MTA1) from MTA-S to MTA1-L. Normally, MTA1-S inhibits cell proliferation by reducing the transcription of cholesterol synthesis genes. In HCC, RALY and SF3B3 cooperate to regulate the MTA1 splicing switch, leading to a reduction in the MTA1-S level, and alleviating the inhibitory effect of MTA1-S on cholesterol synthesis genes, thus promoting HCC cell proliferation. In conclusion, our results revealed that the RALY-SF3B3/MTA1/cholesterol synthesis pathway contributes essentially to hepatic carcinogenesis and could serve as a promising therapeutic target for HCC.

• Authors: Yejun Qiao, Qili Shi, Xu Yuan, Jie Ding, Xinrong Li, Mengting Shen, Shenglin Huang, Zhiao Chen, Lu Wang, Yingjun Zhao, Xianghuo He
• Journal: Cancer letters (Cancer Lett) Vol. 538 Pg. 215711 (07 10 2022) ISSN: 1872-7980 [Electronic] Ireland
• PMID: 35490918 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2022 Elsevier B.V. All rights reserved.

Chemical References

• Heterogeneous-Nuclear Ribonucleoprotein Group C
• MTA1 protein, human
• RALY protein, human
• RNA-Binding Proteins
• Repressor Proteins
• Trans-Activators
• Cholesterol

Topics

• Alternative Splicing
• Carcinogenesis (genetics)
• Carcinoma, Hepatocellular (pathology)
• Cholesterol (biosynthesis)
• Gene Expression Regulation, Neoplastic
• Heterogeneous-Nuclear Ribonucleoprotein Group C (genetics, metabolism)
• Humans
• Liver Neoplasms (pathology)
• RNA-Binding Proteins (genetics)
• Repressor Proteins (genetics, metabolism)
• Trans-Activators (genetics, metabolism)