Mechanical cues control mutant p53 stability through a mevalonate-RhoA axis

Nat Cell Biol. 2018 Jan;20(1):28-35. doi: 10.1038/s41556-017-0009-8. Epub 2017 Dec 18.

Abstract

Tumour-associated p53 missense mutants act as driver oncogenes affecting cancer progression, metastatic potential and drug resistance (gain-of-function) 1 . Mutant p53 protein stabilization is a prerequisite for gain-of-function manifestation; however, it does not represent an intrinsic property of p53 mutants, but rather requires secondary events 2 . Moreover, mutant p53 protein levels are often heterogeneous even within the same tumour, raising questions on the mechanisms that control local mutant p53 accumulation in some tumour cells but not in their neighbours 2,3 . By investigating the cellular pathways that induce protection of mutant p53 from ubiquitin-mediated proteolysis, we found that HDAC6/Hsp90-dependent mutant p53 accumulation is sustained by RhoA geranylgeranylation downstream of the mevalonate pathway, as well as by RhoA- and actin-dependent transduction of mechanical inputs, such as the stiffness of the extracellular environment. Our results provide evidence for an unpredicted layer of mutant p53 regulation that relies on metabolic and mechanical cues.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actins / genetics
  • Actins / metabolism
  • Animals
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology
  • Breast Neoplasms / drug therapy
  • Breast Neoplasms / genetics*
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / pathology
  • Cell Line, Tumor
  • Databases, Factual
  • Female
  • Gene Expression Regulation, Neoplastic*
  • HSP90 Heat-Shock Proteins / genetics
  • HSP90 Heat-Shock Proteins / metabolism
  • Histone Deacetylase 6 / genetics
  • Histone Deacetylase 6 / metabolism
  • Humans
  • Mechanotransduction, Cellular / genetics*
  • Mevalonic Acid / metabolism*
  • Mice
  • Mice, SCID
  • Mutation
  • Protein Stability
  • Proteolysis
  • Small Molecule Libraries / chemistry
  • Small Molecule Libraries / pharmacology
  • Tumor Suppressor Protein p53 / genetics*
  • Tumor Suppressor Protein p53 / metabolism
  • Ubiquitin / genetics
  • Ubiquitin / metabolism
  • Xenograft Model Antitumor Assays
  • rhoA GTP-Binding Protein / genetics*
  • rhoA GTP-Binding Protein / metabolism

Substances

  • Actins
  • Antineoplastic Agents
  • HSP90 Heat-Shock Proteins
  • Small Molecule Libraries
  • Tumor Suppressor Protein p53
  • Ubiquitin
  • RHOA protein, human
  • HDAC6 protein, human
  • Histone Deacetylase 6
  • rhoA GTP-Binding Protein
  • Mevalonic Acid