USP21 deubiquitinase promotes pancreas cancer cell stemness via Wnt pathway activation

Genes Dev. 2019 Oct 1;33(19-20):1361-1366. doi: 10.1101/gad.326314.119. Epub 2019 Sep 5.

Abstract

The ubiquitin-specific protease (USP) family is the largest group of cysteine proteases. Cancer genomic analysis identified frequent amplification of USP21 (22%) in human pancreatic ductal adenocarcinoma (PDAC). USP21 overexpression correlates with human PDAC progression, and enforced expression of USP21 accelerates murine PDAC tumor growth and drives PanIN to PDAC progression in immortalized human pancreatic ductal cells. Conversely, depletion of USP21 impairs PDAC tumor growth. Mechanistically, USP21 deubiquitinates and stabilizes the TCF/LEF transcription factor TCF7, which promotes cancer cell stemness. Our work identifies and validates USP21 as a PDAC oncogene, providing a potential druggable target for this intractable disease.

Keywords: TCF7; USP21; Wnt pathway; cancer stemness; deubiquitinase; pancreatic cancer.

Publication types

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

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Gene Expression Regulation, Neoplastic / genetics*
  • Humans
  • Mice
  • Neoplastic Stem Cells / pathology
  • Pancreatic Neoplasms / enzymology*
  • Pancreatic Neoplasms / genetics
  • Pancreatic Neoplasms / physiopathology
  • T Cell Transcription Factor 1
  • Ubiquitin Thiolesterase / genetics*
  • Ubiquitin Thiolesterase / metabolism*
  • Ubiquitination
  • Wnt Signaling Pathway / genetics*

Substances

  • T Cell Transcription Factor 1
  • TCF7 protein, human
  • USP21 protein, human
  • Ubiquitin Thiolesterase