The HIF/PHF8/AR axis promotes prostate cancer progression

Abstract

Recent studies provide strong evidence that the androgen receptor (AR) signaling pathway remains active in castration-resistant prostate cancer (CRPC). However, the underlying mechanisms are not well understood. In this study, we demonstrate that plant homeo domain finger protein 8 (PHF8 )interacts with and functions as an essential histone demethylase activity-dependent AR coactivator. Furthermore, we demonstrate that the expression of PHF8 is induced by hypoxia in various prostate cancer cell lines. Knockdown of either hypoxia-inducible factor HIF2α or HIF1α almost completely abolished hypoxia-induced PHF8 expression. Importantly, we observed that PHF8 is highly expressed in clinical androgen deprived prostate cancer samples and expression of PHF8 correlates with increased levels of HIF1α and HIF2α. Moreover, elevated PHF8 is associated with higher grade prostate cancers and unfavorable outcomes. Our findings support a working model in which hypoxia in castrated prostate cancer activates HIF transcription factors which then induces PHF8 expression. The elevated PHF8 in turn promotes the AR signaling pathway and prostate cancer progression. Therefore, the HIF/PHF8/AR axis could serve as a potential biomarker for CRPC and is also a promising therapeutic target in combating CRPC.

Histone demethylase PHF8 regulates hypoxia signaling through HIF1α and H3K4me3

“…2A and B). This is consistent with the published data on the upregulation of PHF8 protein [17,18], but not RNA level [17]. We also found that ENO2 was strongly upregulated at later time points (Supplementary Fig.…”

“…However, the c-MYC-miR-22-PHF8 axis is decoupled under hypoxia (1% O 2 , 6 day treatment), with c-MYC downregulated but PHF8 post-transcriptionally upregulated. Recently, it was reported that in the context of hypoxia HIF1α and HIF2α transcriptionally upregulate PHF8, which interacts with AR and enhances its transcriptional activity [18]. In the current study, we report PHF8 plays a critical role in hypoxia signaling as it: positively regulates KDM3A which is a critical coactivator of HIF1α; indirectly sustains H3K4me3 levels on select hypoxia-inducible genes; and is required for full activation of HIF1α through various mechanisms.…”

“…We next asked if PHF8 plays a role in hypoxia signaling in prostate cancer cells, as we and others reported that hypoxia upregulates PHF8 in LNCaP cells [17,18]. A time course of hypoxia (1% O 2 ) treatment in LNCaP cells revealed that the PHF8 protein, but not the mRNA, is slightly upregulated after 24 h, continuing through 6 days (Supplementary Fig.…”

“…A recent study showed that hypoxia (1% O 2 , 24 h) upregulated the levels of PHF8 protein, with marginal upregulation of its mRNA levels in LNCaP cells, and that PHF8 protein maintains its demethylation activity under hypoxia condition [18]. These findings prompted us to question whether PHF8 plays a role in hypoxia signaling.…”

“…This potential link may also explain the mechanism underlying the association of PHF8-mediated regulation of HIF1α with AR status in prostate cancer cells, in part because, activated AR signaling can activate HIF1α through autocrine loop involving EGF/PI3K/PKB [7] or directly through transcriptional regulation [42]. Additional supporting evidence is the recently identified HIF/PHF8/AR axis, in which PHF8 regulates AR target genes under hypoxia [18], thus, it is also possible that PHF8 indirectly regulates HIF1A through AR signaling. A systematic approach is still needed to tackle these possible mechanisms.…”