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Alternative splicing of LSD1+8a is mediated by SRRM4 in Neuroendocrine Prostate Cancer

ABSTRACT: Neuroendocrine prostate cancer (NEPC) is the most virulent subtype. Currently, there is an urgent need to identify new biomarkers and therapeutic targets in NEPC. The splicing factor SRRM4 was previously demonstrated to be highly expressed in NEPC, to promote expression of genes linked to neuroendocrine differentiation and cancer progression, and to promote alternate splicing of genes, including REST. One of REST’s binding protein is lysine specific demethylase 1 (LSD1). Importantly, a transcript variant of LSD1 called LSD1+8a is expressed in neuronal tissues and promotes neuronal gene expression. However, there was no information about LSD1+8a’s importance in prostate cancer. Using adenocarcinoma and NEPC patient-derived xenografts and clinical specimens, we determined that LSD1+8a was expressed exclusively in NEPC. Furthermore, LSD1+8a expression was significantly correlated with elevated mRNA expression of SRRM4. Using SRRM4-overexpressing prostate cancer cell lines, we determined that alternative splicing of LSD1+8a is directly mediated by SRRM4 and that LSD1+8a and SRRM4 co-regulate a unique program of cancer-promoting genes that is not regulated by canonical LSD1. Our findings demonstrate that measurement of LSD1+8a expression is a promising NEPC biomarker and suggest that targeting LSD1+8a in NEPC may be a useful strategy to block expression of genes linked to cancer progression.

ORGANISM(S): Homo sapiens

PROVIDER: GSE132062 | GEO | 2020/05/19

REPOSITORIES: GEO

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Project description:Introduction: Neuroendocrine prostate cancer (NEPC) is an aggressive subtype of prostate cancer, exhibiting rapid progression and is unresponsive to hormone therapy. Reliable prognostic assays and more effective treatments are critically required. However, the research of NEPC has been hampered by a lack of clinically relevant in vivo models. Recently, we successfully developed a first-in-field patient tissue-derived xenograft model of complete neuroendocrine transdifferentiation from prostate adenocarcinoma. By comparing gene expression profiles of the parental adenocarcinoma line (LTL331) and the NEPC subline (LTL331R), we identified DEK, a gene not previously reported in prostate cancer, as a potential biomarker and target for NEPC. Methods: DEK protein expression in patient tissue-derived xenograft models and clinical samples was assessed by immunohistochemistry. The function of DEK was determined by siRNA-induced reduction of DEK expression in PC-3 cells, a cell line with NEPC characteristics, followed by functional assays and gene expression profiling analysis. Results: Elevated DEK protein expression was observed in all clinical NEPC cases, which is distinct from their benign counterparts (0%), hormonal naïve prostate cancer (2.45%) and castration resistant prostate cancer (29.55%). Increased DEK expression is an independent clinical risk factor and is associated with shorter disease free survival in hormonal naïve prostate cancer patients. Reduction of DEK expression in PC-3 cells led to a marked reduction in cell proliferation, cell migration and invasion. Conclusions: The results suggest that DEK may play an important role in the progression of prostate cancer, especially NEPC and provide a potential biomarker to aid risk stratification of prostate cancer and a novel therapeutic target for treating NEPC. The function of DEK was determined by siRNA-induced reduction of DEK expression in PC-3 cells, a cell line with NEPC characteristics, followed by functional assays and gene expression profiling analysis.

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Alternative splicing of LSD1+8a is mediated by SRRM4 in Neuroendocrine Prostate Cancer

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