The mTOR and PP2A Pathways Regulate PHD2 Phosphorylation to Fine-Tune HIF1alpha Levels and Colorectal Cancer Cell Survival under Hypoxia.

Oxygen-dependent HIF1alpha hydroxylation and degradation are strictly controlled by PHD2. In hypoxia, HIF1alpha partly escapes degradation because of low oxygen availability. Here, we show that PHD2 is phosphorylated on serine 125 (S125) by the mechanistic target of rapamycin (mTOR) downstream kinase P70S6K and that this phosphorylation increases its ability to degrade HIF1alpha. mTOR blockade in hypoxia by REDD1 restrains P70S6K and unleashes PP2A phosphatase activity. Through its regulatory subunit B55alpha, PP2A directly dephosphorylates PHD2 on S125, resulting in a further reduction of PHD2 activity that ultimately boosts HIF1alpha accumulation. These events promote autophagy-mediated cell survival in colorectal cancer (CRC) cells. B55alpha knockdown blocks neoplastic growth of CRC cells invitro and invivo in a PHD2-dependent manner. In patients, CRC tissue expresses higher levels of REDD1, B55alpha, and HIF1alpha but has lower phospho-S125 PHD2 compared with a healthy colon. Our data disclose a mechanism of PHD2 regulation that involves the mTOR and PP2A pathways and controls tumor growth.