Chaperones and Ubiquitin Ligases Balance Mutant p53 Protein Stability in Esophageal and Other Digestive Cancers

Cell Mol Gastroenterol Hepatol. 2021;11(2):449-464. doi: 10.1016/j.jcmgh.2020.10.012. Epub 2020 Oct 31.

Abstract

The incidence of esophageal adenocarcinoma (EAC) and other gastrointestinal (GI) cancers have risen dramatically, thus defining the oncogenic drivers to develop effective therapies are necessary. Patients with Barrett's Esophagus (BE), have an elevated risk of developing EAC. Around 70%-80% of BE cases that progress to dysplasia and cancer have detectable TP53 mutations. Similarly, in other GI cancers higher rates of TP53 mutation are reported, which provide a significant survival advantage to dysplastic/cancer cells. Targeting molecular chaperones that mediate mutant p53 stability may effectively induce mutant p53 degradation and improve cancer outcomes. Statins can achieve this via disrupting the interaction between mutant p53 and the chaperone DNAJA1, promoting CHIP-mediated degradation of mutant p53, and statins are reported to significantly reduce the risk of BE progression to EAC. However, statins demonstrated sub-optimal efficacy depending on cancer types and TP53 mutation specificity. Besides the well-established role of MDM2 in p53 stability, we reported that individual isoforms of the E3 ubiquitin ligase GRAIL (RNF128) are critical, tissue-specific regulators of mutant p53 stability in BE progression to EAC, and targeting the interaction of mutant p53 with these isoforms may help mitigate EAC development. In this review, we discuss the critical ubiquitin-proteasome and chaperone regulation of mutant p53 stability in EAC and other GI cancers with future insights as to how to affect mutant p53 stability, further noting how the precise p53 mutation may influence the efficacy of treatment strategies and identifying necessary directions for further research in this field.

Keywords: HSP; Heat Shock Protein; RNF128/GRAIL; UPS; Ubiquitin Proteasome System; p53.

Publication types

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

MeSH terms

  • Antineoplastic Agents / pharmacology*
  • Antineoplastic Agents / therapeutic use
  • Gastrointestinal Neoplasms / drug therapy
  • Gastrointestinal Neoplasms / genetics*
  • Gastrointestinal Neoplasms / pathology
  • Humans
  • Molecular Chaperones / antagonists & inhibitors
  • Molecular Chaperones / metabolism*
  • Molecular Targeted Therapy / methods
  • Mutation
  • Protein Stability / drug effects
  • Proteolysis / drug effects
  • Tumor Suppressor Protein p53 / genetics*
  • Tumor Suppressor Protein p53 / metabolism
  • Ubiquitin-Protein Ligases / antagonists & inhibitors
  • Ubiquitin-Protein Ligases / metabolism*

Substances

  • Antineoplastic Agents
  • Molecular Chaperones
  • TP53 protein, human
  • Tumor Suppressor Protein p53
  • Ubiquitin-Protein Ligases