PGC1α-mediated upregulation of PHD2 represses HIF-signaling, limiting prostate cancer progression.

PPARγ coactivator 1 alpha (PGC1α) is a master transcriptional coregulator of metabolism, and its activity mirrors many of the effects of hypoxia signaling in prostate cancer (PCa). Whereas PGC1α restrains PCa progression through its association with the estrogen-related receptor alpha (ERRα) and is a predictor of better patient outcome, hypoxia signaling is associated with poor prognosis. However, their interplay in PCa remains poorly understood. Here we show that the PGC1α/ERRα complex reduces the protein levels of Hypoxia Inducible transcription Factor alpha (HIFα). Moreover, loss of PGC1α is associated with the establishment of an autocrine pseudohypoxic state. Mechanistically, the transcriptional complex formed by PGC1α and ERRα binds to the EGLN1 promoter, induces PHD2 expression, and triggers canonical HIFα proteasomal degradation. This mechanism is oxygen-dependent and thus is prevented under severe hypoxia. Importantly, this regulatory axis provides a new component to the tumor-suppressive activity of the PGC1α/ERRα complex. Specifically, EGLN1 silencing partially reverts PGC1α-mediated PCa tumor suppressive properties both in cellulo and in vivo. Our findings are reinforced by a positive correlation between PGC1α/ERRα activity and EGLN1 expression levels in human PCa datasets. Altogether, these results support that PHD2-regulated degradation of HIFα contributes to PGC1α/ERRα-mediated PCa suppression.