PHD2 Targeting Overcomes Breast Cancer Cell Death upon Glucose Starvation in a PP2A/B55α-Mediated Manner.
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.
Laboratory of Tumor Inflammation and Angiogenesis, Vesalius Research Center, VIB, 3000 Leuven, Belgium; Laboratory of Tumor Inflammation and Angiogenesis, Department of Oncology, KU Leuven, 3000 Leuven, Belgium. Electronic address: giusy.diconza@unil.ch.
Giusy
G
Di Conza
Laboratory of Tumor Inflammation and Angiogenesis, Vesalius Research Center, VIB, 3000 Leuven, Belgium; Laboratory of Tumor Inflammation and Angiogenesis, Department of Oncology, KU Leuven, 3000 Leuven, Belgium.
Sarah
S
Trusso Cafarello
Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, 450 West Drive, Chapel Hill, NC 27599, USA.
Xingnan
X
Zheng
Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, 450 West Drive, Chapel Hill, NC 27599, USA.
Qing
Q
Zhang
Laboratory of Tumor Inflammation and Angiogenesis, Vesalius Research Center, VIB, 3000 Leuven, Belgium; Laboratory of Tumor Inflammation and Angiogenesis, Department of Oncology, KU Leuven, 3000 Leuven, Belgium. Electronic address: massimiliano.mazzone@vib-kuleuven.be.
Massimiliano
M
Mazzone
D000818:Animals; D017209:Apoptosis; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D005260:Female; D020868:Gene Silencing; D005947:Glucose / Q000172:deficiency*; D057809:HEK293 Cells; D006801:Humans; D006900:Hydroxylation; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases / Q000378:metabolism*; D051379:Mice; D011392:Proline / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D054648:Protein Phosphatase 2 / Q000378:metabolism*; D059748:Proteolysis; D054875:Ubiquitination
C512974:PPP2R2A protein, human; D011392:Proline; C490190:EGLN1 protein, human; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases; D054648:Protein Phosphatase 2; D046988:Proteasome Endopeptidase Complex; D005947:Glucose
PHD2; PP2A; breast cancer; cell death; glucose starvation