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  • Title: RNA Splicing of the BHC80 Gene Contributes to Neuroendocrine Prostate Cancer Progression.
    Author: Li Y, Xie N, Chen R, Lee AR, Lovnicki J, Morrison EA, Fazli L, Zhang Q, Musselman CA, Wang Y, Huang J, Gleave ME, Collins C, Dong X.
    Journal: Eur Urol; 2019 Aug; 76(2):157-166. PubMed ID: 30910347.
    Abstract:
    BACKGROUND: 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. OBJECTIVE: To characterize the role of alternative RNA splicing of the histone demethylase BHC80 during t-NEPC progression. DESIGN, SETTING, AND PARTICIPANTS: 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. RESULTS: 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. CONCLUSIONS: Gain of function of BHC80-2 through alternative RNA splicing activates immune responses of cancer cells to promote t-NEPC development. PATIENT SUMMARY: 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.
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