The PHLPP2 phosphatase is a druggable driver of prostate cancer progression

J Cell Biol. 2019 Jun 3;218(6):1943-1957. doi: 10.1083/jcb.201902048. Epub 2019 May 15.

Abstract

Metastatic prostate cancer commonly presents with targeted, bi-allelic mutations of the PTEN and TP53 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 Pten/Trp53 mutant metastatic prostate cancer, we found that complete loss of Phlpp2 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 PTEN 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Cell Proliferation
  • Disease Progression
  • Humans
  • Male
  • Mice
  • Mice, Knockout
  • Neoplasm Metastasis
  • PTEN Phosphohydrolase / physiology*
  • Phosphoprotein Phosphatases / antagonists & inhibitors
  • Phosphoprotein Phosphatases / physiology*
  • Phosphorylation
  • Prostatic Neoplasms / drug therapy
  • Prostatic Neoplasms / genetics
  • Prostatic Neoplasms / metabolism
  • Prostatic Neoplasms / pathology*
  • Protein Stability
  • Proto-Oncogene Proteins c-akt / genetics
  • Proto-Oncogene Proteins c-akt / metabolism
  • Proto-Oncogene Proteins c-myc / chemistry*
  • Proto-Oncogene Proteins c-myc / genetics
  • Proto-Oncogene Proteins c-myc / metabolism
  • Signal Transduction
  • Small Molecule Libraries / pharmacology*
  • Tumor Cells, Cultured
  • Tumor Suppressor Protein p53 / physiology*

Substances

  • Myc protein, mouse
  • Proto-Oncogene Proteins c-myc
  • Small Molecule Libraries
  • Trp53 protein, mouse
  • Tumor Suppressor Protein p53
  • Proto-Oncogene Proteins c-akt
  • PHLPP2 protein, mouse
  • Phosphoprotein Phosphatases
  • PTEN Phosphohydrolase
  • Pten protein, mouse