PHD2 Targeting Overcomes Breast Cancer Cell Death upon Glucose Starvation in a PP2A/B55α-Mediated Manner

B55 alpha is a regulatory subunit of the PP2A phosphatase. We have recently found that B55 alpha-associated PP2A promotes partial deactivation of the HIF-prolyl-hydroxylase enzyme PHD2. Here, we show that, in turn, PHD2triggers degradation of B55 alpha by hydroxylating it at proline 319. In the context of glucose starvation, PHD2 reduces B55 alpha protein levels, which correlates with MDA-MB231 and MCF7 breast cancer cell death. Under these conditions, PHD2 silencing rescues B55 alpha degradation, overcoming apoptosis, whereas in SKBR3 breast cancer cells showing resistance to glucose starvation, B55 alpha knockdown restores cell death and prevents neoplastic growth in vitro. Treatment of MDA-MB231-derived xenografts with the glucose competitor 2-deoxy-glucose leads to tumor regression in the presence of PHD2. Knockdown of PHD2 induces B55 alpha accumulation and treatment resistance by preventing cell apoptosis. Overall, our data unravel B55a as a PHD2 substrate and highlight a role for PHD2-B55 alpha in the response to nutrient deprivation.