RNA Splicing of the BHC80 Gene Contributes to Neuroendocrine Prostate Cancer Progression

Prostate adenocarcinoma (AdPC) progression to treatment-induced neuroendocrine prostate cancer (t-NEPC) is associated with poor patient survival. While AdPC and t-NEPC share similar genomes, they possess distinct transcriptomes, suggesting that RNA splicing and epigenetic mechanisms may regulate t-N...

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Published in:European urology 2019-08, Vol.76 (2), p.157-166
Main Authors: Li, Yinan, Xie, Ning, Chen, Ruiqi, Lee, Ahn R., Lovnicki, Jessica, Morrison, Emma A., Fazli, Ladan, Zhang, Qingfu, Musselman, Catherine A., Wang, Yuzhuo, Huang, Jiaoti, Gleave, Martin E., Collins, Colin, Dong, Xuesen
Format: Article
Language:English
Subjects:
Adenocarcinoma - genetics
Alternative RNA splicing
Animals
BHC80
Cell Line, Tumor
Cell Proliferation - genetics
Disease Progression
Gene Expression Profiling
Genetic Variation
Histone Deacetylases - genetics
Humans
Male
Mice
Myeloid Differentiation Factor 88 - metabolism
Neoplasm Transplantation
Nerve Tissue Proteins - genetics
Neuroendocrine Tumors - genetics
Neuroendocrine Tumors - metabolism
p38 Mitogen-Activated Protein Kinases - metabolism
Prostatic Neoplasms - genetics
Protein Isoforms - genetics
RNA Splicing
Signal Transduction - genetics
Spheroids, Cellular
SRRM4
Treatment-induced neuroendocrine prostate cancer
Tristetraprolin - metabolism
Tumor Cells, Cultured
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Summary:Prostate adenocarcinoma (AdPC) progression to treatment-induced neuroendocrine prostate cancer (t-NEPC) is associated with poor patient survival. While AdPC and t-NEPC share similar genomes, they possess distinct transcriptomes, suggesting that RNA splicing and epigenetic mechanisms may regulate t-NEPC development. To characterize the role of alternative RNA splicing of the histone demethylase BHC80 during t-NEPC progression. The expression of BHC80 splice variants (BHC80-1 and BHC80-2) were compared between AdPC and t-NEPC patient tumors. Regulatory mechanisms of RNA splicing of the BHC80 gene were studied, and the signal pathways mediated by BHC80 splice variants were investigated in t-NEPC cell and xenograft models. Global transcriptome analyses identified that the BHC80-2 variant is highly expressed in t-NEPC. Compared with the known histone demethylation activities of the BHC80 gene, we discovered a novel nonepigenetic action of BHC80-2, whereby BHC80-2 is localized in the cytoplasm to trigger the MyD88-p38-TTP pathway, which results in increased RNA stability of multiple tumor-promoting cytokines. While BHC80-2 does not induce neuroendocrine differentiation of cancer cells, it stimulates cell proliferation and tumor progression independent of androgen receptor signaling. Blockade of BHC80-2-regulated MyD88 signaling suppresses growth of several t-NEPC cell spheroid and xenograft models. Gain of function of BHC80-2 through alternative RNA splicing activates immune responses of cancer cells to promote t-NEPC development. The main obstacle to develop effective therapies for patients with t-NEPC is the lack of understanding on how t-NEPC is developed. Our study not only identifies a previously unknown BHC80-2-MyD88 signaling pathway that plays an important role during t-NEPC development, but also provides a proof of principle that targeting this signal pathway may offer an avenue to treat t-NEPC. We report that alternative RNA splicing of the histone demethylase BHC80 gene promotes prostate adenocarcinoma progression to treatment-induced neuroendocrine prostate cancer (t-NEPC). Functionally, reprogrammed RNA splice variant of BHC80-2 mediates nonepigenetic actions in cytoplasm, to stimulate multiple tumor-promoting cytokines for t-NEPC development androgen independently.
ISSN:0302-2838
1873-7560
DOI:10.1016/j.eururo.2019.03.011