Faculty Collaboration Database

RNA Splicing of the BHC80 Gene Contributes to Neuroendocrine Prostate Cancer Progression. Eur Urol 2019 Aug;76(2):157-166

Date

03/27/2019

Pubmed ID

30910347

DOI

10.1016/j.eururo.2019.03.011

Scopus ID

2-s2.0-85063207106 (requires institutional sign-in at Scopus site)   20 Citations

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.

Author List

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

Author

Emma A. Morrison PhD Assistant Professor in the Biochemistry department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Adenocarcinoma
Animals
Cell Line, Tumor
Cell Proliferation
Disease Progression
Gene Expression Profiling
Genetic Variation
Histone Deacetylases
Humans
Male
Mice
Myeloid Differentiation Factor 88
Neoplasm Transplantation
Nerve Tissue Proteins
Neuroendocrine Tumors
Prostatic Neoplasms
Protein Isoforms
RNA Splicing
Signal Transduction
Spheroids, Cellular
Tristetraprolin
Tumor Cells, Cultured
p38 Mitogen-Activated Protein Kinases