The PHLPP2 phosphatase is a druggable driver of prostate cancer progression. Academic Article uri icon

Overview

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.

authors

  • Nowak, Dawid
  • Katsenelson, Ksenya Cohen
  • Watrud, Kaitlin E
  • Chen, Muhan
  • Mathew, Grinu
  • D'Andrea, Vincent D
  • Lee, Matthew F
  • Swamynathan, Manojit Mosur
  • Casanova-Salas, Irene
  • Jibilian, Megan C
  • Buckholtz, Caroline L
  • Ambrico, Alexandra J
  • Pan, Chun-Hao
  • Wilkinson, John E
  • Newton, Alexandra C
  • Trotman, Lloyd C

publication date

  • May 15, 2019

Research

keywords

  • PTEN Phosphohydrolase
  • Phosphoprotein Phosphatases
  • Prostatic Neoplasms
  • Proto-Oncogene Proteins c-myc
  • Small Molecule Libraries
  • Tumor Suppressor Protein p53

Identity

PubMed Central ID

  • PMC6548123

Scopus Document Identifier

  • 85067216889

Digital Object Identifier (DOI)

  • 10.1083/jcb.201902048

PubMed ID

  • 31092557

Additional Document Info

volume

  • 218

issue

  • 6