Title | The PHLPP2 phosphatase is a druggable driver of prostate cancer progression. |
Publication Type | Journal Article |
Year of Publication | 2019 |
Authors | Nowak DG, Katsenelson KCohen, Watrud KE, Chen M, Mathew G, D'Andrea VD, Lee MF, Swamynathan MMosur, Casanova-Salas I, Jibilian MC, Buckholtz CL, Ambrico AJ, Pan C-H, Wilkinson JE, Newton AC, Trotman LC |
Journal | J Cell Biol |
Volume | 218 |
Issue | 6 |
Pagination | 1943-1957 |
Date Published | 2019 06 03 |
ISSN | 1540-8140 |
Keywords | Animals, Cell Proliferation, Disease Progression, Humans, Male, Mice, Mice, Knockout, Neoplasm Metastasis, Phosphoprotein Phosphatases, Phosphorylation, Prostatic Neoplasms, Protein Stability, Proto-Oncogene Proteins c-akt, Proto-Oncogene Proteins c-myc, PTEN Phosphohydrolase, Signal Transduction, Small Molecule Libraries, Tumor Cells, Cultured, Tumor Suppressor Protein p53 |
Abstract | Metastatic prostate cancer commonly presents with targeted, bi-allelic mutations of the and tumor suppressor genes. In contrast, however, most candidate tumor suppressors are part of large recurrent hemizygous deletions, such as the common chromosome 16q deletion, which involves the AKT-suppressing phosphatase PHLPP2. Using RapidCaP, a genetically engineered mouse model of mutant metastatic prostate cancer, we found that complete loss of paradoxically blocks prostate tumor growth and disease progression. Surprisingly, we find that Phlpp2 is essential for supporting Myc, a key driver of lethal prostate cancer. Phlpp2 dephosphorylates threonine-58 of Myc, which renders it a limiting positive regulator of Myc stability. Furthermore, we show that small-molecule inhibitors of PHLPP2 can suppress MYC and kill mutant cells. Our findings reveal that the frequent hemizygous deletions on chromosome 16q present a druggable vulnerability for targeting MYC protein through PHLPP2 phosphatase inhibitors. |
DOI | 10.1083/jcb.201902048 |
Alternate Journal | J Cell Biol |
PubMed ID | 31092557 |
PubMed Central ID | PMC6548123 |
Grant List | R01 CA137050 / CA / NCI NIH HHS / United States R35 GM122523 / GM / NIGMS NIH HHS / United States P50 CA211024 / CA / NCI NIH HHS / United States T32 CA009523 / CA / NCI NIH HHS / United States P30 CA045508 / CA / NCI NIH HHS / United States R01 GM065490 / GM / NIGMS NIH HHS / United States |