Histone demethylase PHF8 regulates hypoxia signaling through HIF1α and H3K4me3

Hypoxia through transcription factor HIF1 alpha plays a critical role in cancer development. In prostate cancer, HIF1 alpha 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 HIF1 alpha. 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 HIF1a and the induction of HIF1 alpha 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 HIF1a. Therefore, targeting PHF8 can potentially be a novel therapeutic strategy in cancer therapy.