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...
| Main Authors: | , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2017-03-01
|
| Series: | Cell Reports |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124717303017 |
| _version_ | 1811227772677259264 |
|---|---|
| author | Giusy Di Conza Sarah Trusso Cafarello Xingnan Zheng Qing Zhang Massimiliano Mazzone |
| author_facet | Giusy Di Conza Sarah Trusso Cafarello Xingnan Zheng Qing Zhang Massimiliano Mazzone |
| author_sort | Giusy Di Conza |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-12T09:46:22Z |
| format | Article |
| id | doaj.art-2bc3fe8430ad4b25af03e1bf1ef339fb |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-04-12T09:46:22Z |
| publishDate | 2017-03-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-2bc3fe8430ad4b25af03e1bf1ef339fb2022-12-22T03:37:55ZengElsevierCell Reports2211-12472017-03-0118122836284410.1016/j.celrep.2017.02.081PHD2 Targeting Overcomes Breast Cancer Cell Death upon Glucose Starvation in a PP2A/B55α-Mediated MannerGiusy Di Conza0Sarah Trusso Cafarello1Xingnan Zheng2Qing Zhang3Massimiliano Mazzone4Laboratory of Tumor Inflammation and Angiogenesis, Vesalius Research Center, VIB, 3000 Leuven, BelgiumLaboratory of Tumor Inflammation and Angiogenesis, Vesalius Research Center, VIB, 3000 Leuven, BelgiumLineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, 450 West Drive, Chapel Hill, NC 27599, USALineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, 450 West Drive, Chapel Hill, NC 27599, USALaboratory of Tumor Inflammation and Angiogenesis, Vesalius Research Center, VIB, 3000 Leuven, BelgiumB55α 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.http://www.sciencedirect.com/science/article/pii/S2211124717303017glucose starvationPP2APHD2breast cancercell death |
| spellingShingle | Giusy Di Conza Sarah Trusso Cafarello Xingnan Zheng Qing Zhang Massimiliano Mazzone PHD2 Targeting Overcomes Breast Cancer Cell Death upon Glucose Starvation in a PP2A/B55α-Mediated Manner Cell Reports glucose starvation PP2A PHD2 breast cancer cell death |
| title | PHD2 Targeting Overcomes Breast Cancer Cell Death upon Glucose Starvation in a PP2A/B55α-Mediated Manner |
| title_full | PHD2 Targeting Overcomes Breast Cancer Cell Death upon Glucose Starvation in a PP2A/B55α-Mediated Manner |
| title_fullStr | PHD2 Targeting Overcomes Breast Cancer Cell Death upon Glucose Starvation in a PP2A/B55α-Mediated Manner |
| title_full_unstemmed | PHD2 Targeting Overcomes Breast Cancer Cell Death upon Glucose Starvation in a PP2A/B55α-Mediated Manner |
| title_short | PHD2 Targeting Overcomes Breast Cancer Cell Death upon Glucose Starvation in a PP2A/B55α-Mediated Manner |
| title_sort | phd2 targeting overcomes breast cancer cell death upon glucose starvation in a pp2a b55α mediated manner |
| topic | glucose starvation PP2A PHD2 breast cancer cell death |
| url | http://www.sciencedirect.com/science/article/pii/S2211124717303017 |
| work_keys_str_mv | AT giusydiconza phd2targetingovercomesbreastcancercelldeathuponglucosestarvationinapp2ab55amediatedmanner AT sarahtrussocafarello phd2targetingovercomesbreastcancercelldeathuponglucosestarvationinapp2ab55amediatedmanner AT xingnanzheng phd2targetingovercomesbreastcancercelldeathuponglucosestarvationinapp2ab55amediatedmanner AT qingzhang phd2targetingovercomesbreastcancercelldeathuponglucosestarvationinapp2ab55amediatedmanner AT massimilianomazzone phd2targetingovercomesbreastcancercelldeathuponglucosestarvationinapp2ab55amediatedmanner |