USP21 deubiquitinase promotes pancreas cancer cell stemness via Wnt pathway activation
- Pingping Hou1,
- Xingdi Ma1,
- Qiang Zhang1,
- Chang-Jiun Wu2,
- Wenting Liao1,3,
- Jun Li2,
- Huamin Wang4,5,
- Jun Zhao5,
- Xin Zhou1,
- Carolyn Guan6,
- Jeffery Ackroyd7,
- Shan Jiang8,
- Jianhua Zhang2,
- Denise J. Spring1,
- Y. Alan Wang1 and
- Ronald A. DePinho1
- 1Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77054, USA;
- 2Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas 77054, USA;
- 3Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China;
- 4Department of Anatomical Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77054, USA;
- 5Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77054, USA;
- 6Princeton University, Princeton, New Jersey 08544, USA;
- 7Department of Cancer Systems Imaging, The University of Texas MD Anderson Cancer Center, Houston, Texas 77054, USA;
- 8Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, Texas 77054, USA
- Corresponding authors: rdepinho{at}mdanderson.org, yalanwang{at}mdanderson.org
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.
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Footnotes
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Supplemental material is available for this article.
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Article published online ahead of print. Article and publication date are online at http://www.genesdev.org/cgi/doi/10.1101/gad.326314.119.
- Received March 8, 2019.
- Accepted August 12, 2019.
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