Journal
ONCOTARGET
Volume 7, Issue 46, Pages 75585-75602Publisher
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.12310
Keywords
prostate cancer; NED; CRPC; PHF8; c-MYC
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Funding
- Department of Anatomy and Cell Biology, the Carver College of Medicine, The University of Iowa
- Carver Trust Young Investigator Award from the Roy. J. Carver Charitable Trust [01-224]
- ACS-IRG seed grant from the American Cancer Society [IRG-77-004-34]
- University of Iowa ICTS (Institute for Clinical and Translational Science)
- University of Iowa ICTS (CTSA grant) [UL1RR024979]
- NIH [P30 CA86862]
- University of Iowa ICTS (NIH)
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Epigenetic factors play critical roles in prostate cancer (PCa) development. However, how they contribute to neuroendocrine differentiation (NED) and castration-resistant PCa (CRPC) is not fully understood. Using bioinformatics and biochemical approaches to analyze cell-based models of NED and CRPC, we found a cluster of epigenetic factors whose expression is downregulated during NED and upregulated in CRPC (i.e. follow a Down-Up pattern). Two histone demethylases within this cluster, PHF8 and KDM3A, are post-transcriptionally regulated by c-MYC through miR-22, which targets both PHF8 and KDM3A. We also found that the c-MYC/miR22/PHF8 axis is downstream of androgen receptor (AR) signaling in CRPC cells. The co-expression of PHF8 with AR in clinical CRPC samples, normal mouse prostate, and adenocarcinomas of the prostate during PCa progression in a transgenic (TRAMP) mouse model supports the connection between PHF8 and AR. Knockdown of PHF8 impedes cell cycle progression in CRPC cells and has more profound effects on their growth than on the parental LNCaP cell line. Furthermore, PHF8 knockdown sensitizes LNCaP-Abl cells to the AR antagonist enzalutamide. Our data reveal novel mechanisms that underlie the regulation of PHF8 and KDM3A during NED and in CRPC, and support the candidacy of PHF8 as a therapeutic target in CRPC.
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