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Investigating the roles of SRRM4 in contribution to neuroendocrine prostate cancer progression Li, Yinan

Abstract

While androgen receptor pathway inhibition (ARPI) has significantly increased the survival of metastatic prostate adenocarcinoma (AdPC), accumulating evidence suggests that AdPC can change to a more aggressive subtype, called treatment-induced neuroendocrine prostate cancer (t-NEPC). T-NEPC is androgen receptor (AR) indifferent, and shows a neuroendocrine-like phenotype. Few targeted therapy is currently available for t-NEPC. It is imperative to identify biomarkers for early detection of t-NEPC and molecular targets for drug development. In this work, using whole transcriptome sequencing on t-NEPC from two independent patient cohorts, we have identified a t-NEPC specific splice signature that is predominantly controlled by the RNA splicing factor, serine/arginine repetitive matrix 4 (SRRM4). We have found that SRRM4 is highly expressed in t-NEPC and is strongly correlated with t-NEPC biomarker expression. Significantly, we have, for the first time, shown that SRRM4 can transform LNCaP adenocarcinoma cells into t-NEPC xenografts. We also confirmed that one of SRRM4 target genes was the RE1 silencing transcription factor (REST), a key regulator of neurogenesis. Moreover, The ARPI combined with a gain of SRRM4-induced adenocarcinoma cells to assume multicellular spheroid morphology, and this was essential in establishing progressive NEPC xenografts. We also identified a BHC80 splice variant, BHC80-2, that functions as a key facilitator of t-NEPC development. Functionally reprogrammed by the SRRM4, BHC80-2 does not confer the NEPC phenotype to cancer cells, but rather stimulates cell proliferation and invasion to accelerate tumor progression. In contrast to the epigenetic role of BHC80 in histone demethylation, we defined a novel non-epigenetic action of BHC80-2, whereby cytosolic BHC80-2 proteins trigger the MyD88-p38-TTP pathway to increase the RNA stability of a set of tumor-promoting cytokines. Blocking BHC80-2 signaling suppresses NEPC cell spheroid growth, identifying BHC80-2 as a potential therapeutic target for t-NEPC. Overall, my doctoral studies confirmed that SRRM4 is both a biomarker and a driver of t-NEPC by regulating tumor cell growth and metastasis in addition to its previously reported roles in neuroendocrine differentiation. Our studies not only enhance our understanding of the mechanisms of NEPC development, but also provide insights for personalized medicine-based strategies for prostate cancer patients.

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Attribution-NonCommercial-NoDerivatives 4.0 International

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