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

Publication date: 21 March 2017
Source:Cell Reports, Volume 18, Issue 12
Author(s): Giusy Di Conza, Sarah Trusso Cafarello, Xingnan Zheng, Qing Zhang, Massimiliano Mazzone
B55α is a regulatory subunit of the PP2A phosphatase. We have recently found that B55α-associated PP2A promotes partial deactivation of the HIF-prolyl-hydroxylase enzyme PHD2. Here, we show that, in turn, PHD2 triggers degradation of B55α by hydroxylating it at proline 319. In the context of glucose starvation, PHD2 reduces B55α protein levels, which correlates with MDA-MB231 and MCF7 breast cancer cell death. Under these conditions, PHD2 silencing rescues B55α degradation, overcoming apoptosis, whereas in SKBR3 breast cancer cells showing resistance to glucose starvation, B55α 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 B55α accumulation and treatment resistance by preventing cell apoptosis. Overall, our data unravel B55α as a PHD2 substrate and highlight a role for PHD2-B55α in the response to nutrient deprivation.

Graphical abstract

Teaser

Di Conza et al. show that, following glucose starvation, a high αKG-to-fumarate ratio favors PHD2 activation that promotes apoptosis by degrading B55α. In breast cancer cells, PHD2 knockdown prevents B55α degradation and overcomes apoptosis in response to glucose starvation. PHD2-silenced MDA-MB231 xenografts show accumulation of B55α and resistance to 2DG treatment.


http://ift.tt/2n5OGn3