c-MYC drives histone demethylase PHF8 during neuroendocrine differentiation and in castration-resistant prostate cancer

被引:45
|
作者
Maina, Peterson Kariuki [1 ]
Shao, Peng [1 ]
Liu, Qi [1 ]
Fazli, Ladan [2 ]
Tyler, Scott [1 ]
Nasir, Moman [3 ]
Dong, Xuesen [2 ]
Qi, Hank Heng [1 ]
机构
[1] Univ Iowa, Carver Coll Med, Dept Anat & Cell Biol, Iowa City, IA 52246 USA
[2] Univ British Columbia, Dept Urol Sci, Vancouver Prostate Ctr, Vancouver, BC V6H 3Z6, Canada
[3] Univ Iowa, Coll Liberal Arts & Sci, Dept Hlth & Human Physiol, Iowa City, IA 52242 USA
关键词
prostate cancer; NED; CRPC; PHF8; c-MYC; ANDROGEN-RECEPTOR; GENE-EXPRESSION; CLIP-SEQ; INTERLEUKIN-6; TRANSCRIPTION; ACTIVATION; GROWTH; CELLS; IDENTIFICATION; REPRESSION;
D O I
10.18632/oncotarget.12310
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
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.
引用
收藏
页码:75585 / 75602
页数:18
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