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RNA splicing of the BHC80 gene contributes to neuroendocrine prostate cancer progression

  • Yinan Li 1,
  • Ning Xie 1,
  • Ruiqi Chen 1,
  • Ahn R. Lee 1,
  • Jessica Lovnicki 1,
  • Emma A. Morrison 2,
  • Ladan Fazli 1,
  • Qingfu Zhang 3,
  • Catherine A. Musselman 2,
  • Yuzhuo Wang 1,
  • Jiaoti Huang 3,
  • Martin E. Gleave 1,
  • Colin Collins 1,
  • Xuesen Dong 1
1 Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada 2 Department of Biochemistry, Carver College of Medicine, University of Iowa, Iowa City, IA, USA 3 Department of Pathology, Duke University School of Medicine, Durham, NC, USA

Publication: European Urology, March 2019

DOI: https://doi.org/10.1016/j.eururo.2019.03.011


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.

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.

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.

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.