1. Histone demethylase PHF8 regulates hypoxia signaling through HIF1α and H3K4me3.
- Author
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Maina PK, Shao P, Jia X, Liu Q, Umesalma S, Marin M, Long D Jr, Concepción-Román S, and Qi HH
- Subjects
- CRISPR-Cas Systems physiology, Cell Line, Cell Proliferation physiology, Clustered Regularly Interspaced Short Palindromic Repeats physiology, Gene Expression Regulation physiology, HEK293 Cells, Humans, Jumonji Domain-Containing Histone Demethylases metabolism, Lysine metabolism, Neuroendocrine Cells metabolism, RNA, Long Noncoding metabolism, Receptors, Androgen metabolism, Transcription, Genetic physiology, Basic Helix-Loop-Helix Transcription Factors metabolism, Histone Demethylases metabolism, Histones metabolism, Hypoxia metabolism, Signal Transduction physiology, Transcription Factors metabolism
- Abstract
Hypoxia through transcription factor HIF1α plays a critical role in cancer development. In prostate cancer, HIF1α interplays with androgen receptor (AR) to contribute to the progression of this disease to its lethal form-castration-resistant prostate cancer (CRPC). Hypoxia upregulates several epigenetic factors including histone demethylase KDM3A which is a critical co-factor of HIF1α. However, how histone demethylases regulate hypoxia signaling is not fully understood. Here, we report that histone demethylase PHF8 plays an essential role in hypoxia signaling. Knockdown or knockout of PHF8 by RNAi or CRISPR-Cas9 system reduced the activation of HIF1α and the induction of HIF1α target genes including KDM3A. Mechanistically, PHF8 regulates hypoxia inducible genes mainly through sustaining the level of trimethylated histone 3 lysine 4 (H3K4me3), an active mark in transcriptional regulation. The positive role of PHF8 in hypoxia signaling extended to hypoxia-induced neuroendocrine differentiation (NED), wherein PHF8 cooperates with KDM3A to regulate the expression of NED genes. Moreover, we discovered that the role of PHF8 in hypoxia signaling is associated with the presence of full-length AR in CRPC cells. Collectively, our study identified PHF8 as a novel epigenetic factor in hypoxia signaling, and the underlying regulatory mechanisms likely apply to general cancer development involving HIF1α. Therefore, targeting PHF8 can potentially be a novel therapeutic strategy in cancer therapy., (Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.)
- Published
- 2017
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