SRSF10 stabilizes CDC25A by triggering exon 6 skipping to promote hepatocarcinogenesis

Journal of Experimental & Clinical Cancer Research

Research

Canxia Xu¹  Fen Wang¹  Yuxing Zhu²  Xingyu Chen²  Mengqing Xiao²  Ke Cao²  Xiaoming Liu³  Yongqiang Zheng⁴  Zexian Liu⁴ 

[1] Department of Gastroenterology, Third Xiangya Hospital of Central South University, 410013, Changsha, China;Department of Oncology, Third Xiangya Hospital of Central South University, 410013, Changsha, China;Department of Oncology, Third Xiangya Hospital of Central South University, 410013, Changsha, China;Department of Gastroenterology, Third Xiangya Hospital of Central South University, 410013, Changsha, China;State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, 510060, Guangzhou, China;

关键词: SRSF10;    CDC25A;    Alternative splicing;    Exon skipping;    Hepatocellular carcinoma;   

DOI  :  10.1186/s13046-022-02558-0

 received in 2022-08-13, accepted in 2022-12-02,  发布年份 2022

来源: Springer

【 摘 要 】

BackgroundAlternative splicing (AS) events are extensively involved in the progression of diverse tumors, but how serine/arginine-rich splicing Factor 10 (SRSF10) behaves in hepatocellular carcinoma (HCC) has not been sufficiently studied. We aimed to determine SRSF10 associated AS mechanisms and their effects on HCC progression.MethodsThe expression of SRSF10 in HCC tissues was examined, and the in vitro and in vivo functions of SRSF10 were investigated. The downstream AS targets were screened using RNA sequencing. The interaction between SRSF10 protein and exclusion of cell division cycle 25 A (CDC25A) mRNA was identified using RNA immunoprecipitation and crosslinking immunoprecipitation q-PCR. The effects of SRSF10 on CDC25A posttranslational modification, subcellular distribution, and protein stability were verified through coimmunoprecipitation, immunofluorescence, and western blotting.ResultsSRSF10 was enriched in HCC tissues and facilitated HCC proliferation, cell cycle, and invasion. RNA sequencing showed that SRSF10 promotes exon 6 exclusion of CDC25A pre-mRNA splicing. As a crucial cell cycle mediator, the exon-skipped isoform CDC25A(△E6) was identified to be stabilized and retained in the nucleus due to the deletion of two ubiquitination (Lys150, Lys169) sites in exon 6. The stabilized isoform CDC25A(△E6) derived from AS had stronger cell cycle effects on HCC tumorigenesis, and playing a more significant role than the commonly expressed longer variant CDC25A(L). Interestingly, SRSF10 activated the carcinogenesis role of CDC25A through Ser178 dephosphorylation to cause nuclear retention. Moreover, CDC25A(△E6) was verified to be indispensable for SRSF10 to promote HCC development in vitro and in vivo.ConclusionsWe reveal a regulatory pattern whereby SRSF10 contributes to a large proportion of stabilized CDC25A(△E6) production, which is indispensable for SRSF10 to promote HCC development. Our findings uncover AS mechanisms such as CDC25A that might serve as potential therapeutic targets to treat HCC.

【 授权许可】

CC BY   
© The Author(s) 2022

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