Proteasome machinery is instrumental in a common gain-of-function program of the p53 missense mutants in cancer

Nat Cell Biol. 2016 Aug;18(8):897-909. doi: 10.1038/ncb3380. Epub 2016 Jun 27.

Abstract

In cancer, the tumour suppressor gene TP53 undergoes frequent missense mutations that endow mutant p53 proteins with oncogenic properties. Until now, a universal mutant p53 gain-of-function program has not been defined. By means of multi-omics: proteome, DNA interactome (chromatin immunoprecipitation followed by sequencing) and transcriptome (RNA sequencing/microarray) analyses, we identified the proteasome machinery as a common target of p53 missense mutants. The mutant p53-proteasome axis globally affects protein homeostasis, inhibiting multiple tumour-suppressive pathways, including the anti-oncogenic KSRP-microRNA pathway. In cancer cells, p53 missense mutants cooperate with Nrf2 (NFE2L2) to activate proteasome gene transcription, resulting in resistance to the proteasome inhibitor carfilzomib. Combining the mutant p53-inactivating agent APR-246 (PRIMA-1MET) with the proteasome inhibitor carfilzomib is effective in overcoming chemoresistance in triple-negative breast cancer cells, creating a therapeutic opportunity for treatment of solid tumours and metastasis with mutant p53.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology
  • Humans
  • Mice
  • MicroRNAs / genetics
  • Mutant Proteins / drug effects*
  • Mutant Proteins / genetics
  • Mutation, Missense / drug effects*
  • Mutation, Missense / genetics
  • NF-E2-Related Factor 2 / genetics
  • NF-E2-Related Factor 2 / metabolism
  • Neoplasm Metastasis / drug therapy
  • Neoplasm Metastasis / genetics
  • Oligopeptides / pharmacology
  • Proteasome Endopeptidase Complex / drug effects*
  • Proteasome Endopeptidase Complex / genetics
  • Proteome / drug effects
  • Quinuclidines / pharmacology
  • Triple Negative Breast Neoplasms / drug therapy
  • Triple Negative Breast Neoplasms / genetics
  • Tumor Suppressor Protein p53 / genetics*
  • Tumor Suppressor Protein p53 / metabolism

Substances

  • 2-hydroxymethyl-2-methoxymethylazabicyclo(2.2.2)octan-3-one
  • Antineoplastic Agents
  • MicroRNAs
  • Mutant Proteins
  • NF-E2-Related Factor 2
  • NFE2L2 protein, human
  • Oligopeptides
  • Proteome
  • Quinuclidines
  • Tumor Suppressor Protein p53
  • carfilzomib
  • Proteasome Endopeptidase Complex