SF3B4 promotes Twist1 expression and clear cell renal cell carcinoma progression by facilitating the export of KLF 16 mRNA from the nucleus to the cytoplasm.

Abstract

Splicing factor 3B subunit 4 (SF3B4) plays important functional roles not only in pre-mRNA splicing, but also in the regulation of transcription, translation, and cell signaling, and its dysregulation contributes to various diseases including Nager syndrome and tumorigenesis. However, the role of SF3B4 and underlying mechanisms in clear cell renal cell carcinoma (ccRCC) remain obscure. In the present study, we found that the expression of SF3B4 was significantly elevated in ccRCC tissues and negatively correlated with the overall survival of ccRCC patients. Upregulation of SF3B4 promotes migration and invasion of ccRCC cells in vitro and in vivo. The promoting effect of SF3B4 on cell migration and invasion is mediated by Twist1, a key transcription factor to mediate EMT. Interestingly, SF3B4, a component of the pre-mRNA spliceosome, is able to promote KLF16 expression by facilitating the transport of KLF16 mRNA into the cytoplasm. Mechanistically, SF3B4 promotes the export of KLF16 mRNA from the nucleus to the cytoplasm and thus enhances KLF16 expression, and in turn elevated KLF16 directly binds to the Twist1 promoter to activate its transcription, leading to EMT and ccRCC progression. Our findings provide evidence that the SF3B4-KLF16-Twist1 axis plays important functional roles in the development and progression of ccRCC, and manipulating this pathway may be a novel therapeutic target for the treatment of ccRCC.

• Authors: Zhan Yang, Ya-Xuan Wang, Jin-Kun Wen, Hai-Tao Gao, Zhen-Wei Han, Jin-Chun Qi, Jun-Fei Gu, Chen-Ming Zhao, Hong Zhang, Bei Shi, Dan-Dan Wang, Xiao-Lu Wang, Chang-Bao Qu
• Journal: Cell death & disease (Cell Death Dis) Vol. 14 Issue 1 Pg. 26 (01 13 2023) ISSN: 2041-4889 [Electronic] England
• PMID: 36639679 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2023. The Author(s).

Chemical References

• RNA Precursors
• RNA, Messenger
• TWIST1 protein, human
• Nuclear Proteins
• Twist-Related Protein 1
• KLF16 protein, human
• Kruppel-Like Transcription Factors
• SF3B4 protein, human
• RNA Splicing Factors

Topics

• Humans
• Carcinoma, Renal Cell (metabolism)
• RNA Precursors (metabolism)
• RNA, Messenger (genetics)
• Cytoplasm (metabolism)
• Cell Line, Tumor
• Kidney Neoplasms (metabolism)
• Cell Proliferation
• Gene Expression Regulation, Neoplastic
• Nuclear Proteins (genetics, metabolism)
• Twist-Related Protein 1 (genetics, metabolism)
• Kruppel-Like Transcription Factors (metabolism)
• RNA Splicing Factors (genetics, metabolism)