Roles of Alternative RNA Splicing of the Bif-1 Gene by SRRM4 During the Development of Treatment-induced Neuroendocrine Prostate Cancer

EBioMedicine
Yu GanXuesen Dong

Abstract

Treatment-induced neuroendocrine prostate cancer (t-NEPC) is an aggressive subtype of prostate cancer (PCa) that becomes more prevalent when hormonal therapy, chemotherapy, or radiation therapy is applied to patients with metastatic prostate adenocarcinoma (AdPC). How AdPC cells survive these anti-cancer therapies and progress into t-NEPC remains unclear. By comparing the whole transcriptomes between AdPC and t-NEPC, we identified Bif-1, an apoptosis-associated gene, which undergoes alternative RNA splicing in t-NEPC. We found that while Bif-1a is the predominant variant of the Bif-1 gene in AdPC, two neural-specific variants, Bif-1b and Bif-1c, are highly expressed in t-NEPC patients, patient derived xenografts, and cell models. The neural-specific RNA splicing factor, SRRM4, promotes Bif-1b and Bif-1c splicing, and the expression of SRRM4 in tumors is strongly associated with Bif-1b/-1c levels. Furthermore, we showed that Bif-1a is pro-apoptotic, while Bif-1b and Bif-1c are anti-apoptotic in PCa cells under camptothecin and UV light irritation treatments. Taken together, our data indicate that SRRM4 regulates alternative RNA splicing of the Bif-1 gene that enables PCa cells resistant to apoptotic stimuli under anti-cancer the...Continue Reading

Citations

Feb 23, 2020·Proceedings of the National Academy of Sciences of the United States of America·John W PhillipsYi Xing
Aug 30, 2018·The Prostate·Yinan LiXuesen Dong
Jul 25, 2020·Current Topics in Medicinal Chemistry·Nidhi ShuklaPrashanth Suravajhala

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Methods Mentioned

BETA
xenograft
Xenografts
Transfection
immunoprecipitation
RNA-seq
PCR
reverse transcription PCR

Software Mentioned

GraphPad
GraphPad Prism
Integrative Genomics Viewer ( IGV )

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