c-MYC drives histone demethylase PHF8 during neuroendocrine differentiation and in castration-resistant prostate cancer.
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/miR-22/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.
Department of Anatomy and Cell Biology, Carver College of Medicine, University of Iowa, Iowa City, IA 52246, USA.
Peterson Kariuki
PK
Maina
Department of Anatomy and Cell Biology, Carver College of Medicine, University of Iowa, Iowa City, IA 52246, USA.
Peng
P
Shao
Department of Anatomy and Cell Biology, Carver College of Medicine, University of Iowa, Iowa City, IA 52246, USA.
Qi
Q
Liu
Vancouver Prostate Center, Department of Urology Sciences, University of British Columbia, Vancouver, BC V6H 3Z6, Canada.
Ladan
L
Fazli
Department of Anatomy and Cell Biology, Carver College of Medicine, University of Iowa, Iowa City, IA 52246, USA.
Scott
S
Tyler
Department of Health and Human Physiology, College of Liberal Arts and Sciences, University of Iowa, Iowa City, IA 52242, USA.
Moman
M
Nasir
Vancouver Prostate Center, Department of Urology Sciences, University of British Columbia, Vancouver, BC V6H 3Z6, Canada.
Xuesen
X
Dong
Department of Anatomy and Cell Biology, Carver College of Medicine, University of Iowa, Iowa City, IA 52246, USA.
Hank Heng
HH
Qi
D020413:3' Untranslated Regions; D000818:Animals; D002453:Cell Cycle / Q000187:drug effects / Q000235:genetics; D059447:Cell Cycle Checkpoints / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics; D002470:Cell Survival / Q000235:genetics; D044127:Epigenesis, Genetic; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D016259:Genes, myc; D056466:Histone Demethylases / Q000235:genetics*; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism / Q000494:pharmacology; D056484:Jumonji Domain-Containing Histone Demethylases / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D035683:MicroRNAs / Q000235:genetics; D008954:Models, Biological; D060787:Neoplasm Grading; D018358:Neuroendocrine Tumors / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D064129:Prostatic Neoplasms, Castration-Resistant / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D034622:RNA Interference; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics*; D059467:Transcriptome
D020413:3' Untranslated Regions; D015850:Interleukin-6; C548375:MIRN22 microRNA, human; D035683:MicroRNAs; D011944:Receptors, Androgen; D014157:Transcription Factors; D056466:Histone Demethylases; D056484:Jumonji Domain-Containing Histone Demethylases; C530247:KDM3A protein, human; C511934:PHF8 protein, human
CRPC; NED; PHF8; c-MYC; prostate cancer
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