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The multifaceted roles of serine/arginine repetitive matrix 4 in the development of neuroendocrine prostate cancer

University of British Columbia

As the clinical burdens of a lethal and therapy-resistant subtype of prostate cancer called treatment-induced neuroendocrine prostate cancer (t-NEPC) are increasing, delineating the molecular underpinnings of t-NEPC will be paramount in developing clinical strategies for this disease course. Recently, t-NEPC-unique RNA-splicing signatures, predominately facilitated by SRRM4, have been characterized. SRRM4 is an RNA-splicing factor that promotes progenitor cell differentiation via neural-specific exon networks essential for functional reprogramming of proteins required for neurogenesis. SRRM4 can transform prostate adenocarcinoma cells into t-NEPC xenografts under castration via a neuroendocrine transdifferentiation mechanism. Given the essential roles of SRRM4 during neurogenesis, we hypothesize that SRRM4 can ultimately promote neuroendocrine reprogramming in different cell types by neural-specific exon networks that contribute to t-NEPC progression. Given the cellular heterogeneity of prostate tumours, this work investigates the functions of SRRM4 in various prostate adenocarcinoma cell lines. We show that SRRM4 ultimately promotes neural-specific transcriptome and splicing programs across all tested cell lines. We also uncover a novel mechanism whereby SRRM4 facilitates t-NEPC development via a pluripotency gene network in DU145 cells that closely recapitulates the molecular and cellular phenotypes of clinical t-NEPC. Furthermore, we characterize the downstream functional consequences of SRRM4-mediated alternative splicing of t-NEPC-unique MEAF6 and GIT1 transcripts. We report a novel facet of SRRM4 in promoting t-NEPC development—invasion and migration via MEAF6 splicing and focal adhesion-mediated signaling and stability via GIT1 splicing. Moreover, we reveal that the t-NEPC-specific MEAF6 isoform promotes cell proliferation and tumorigenesis. These studies demonstrate an important role of SRRM4-mediated RNA alternative splicing of MEAF6 and GIT1 in its contributions to the multifaceted processes of t-NEPC development such as cell proliferation, clonal expansion, and invasion/metastasis. This thesis work adds to an understudied field of alternative splicing and its importance in the t-NEPC disease progression. My findings suggest a role of SRRM4 and SRRM4-mediated splicing signatures (i.e. MEAF6/GIT1) as potential biomarkers of t-NEPC and support the notion that SRRM4 is an important facilitator of t-NEPC development. Ultimately this knowledge pertains to the clinical implications of SRRM4 and SRRM4-mediated splicing in informing future therapies that will be effective in detecting, preventing, or managing t-NEPC.

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2019-04-16

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/69803

Reproductive and Developmental Sciences

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/