USP21 deubiquitinase promotes pancreas cancer cell stemness via Wnt pathway activation
Open accessAbstract
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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USP21 overexpression also upregulates mTOR-related signaling pathways.
“USP21 overexpression also upregulates mTOR-related signaling pathways.”
From Targeting KRAS mutant cancers: from druggable therapy to drug resistance (2022) · cites this paper as [51]
USP21 is expected to be a viable therapeutic target in PDAC, either as monotherapy or in combination with inhibitors targeting KRAS mutation.
“Therefore, USP21 is expected to be a viable therapeutic target in PDAC, either as monotherapy or in combination with inhibitors targeting KRAS mutation [51, 52].”
From Targeting KRAS mutant cancers: from druggable therapy to drug resistance (2022) · cites this paper as [51]
Hou et al. revealed that USP21 increases macropinocytosis by microtubule-affinity-regulating kinase 3 (MARK3), thus providing metabolic support after KRAS mutation extinction in PDAC cancer cells.
“Furthermore, Hou et al. revealed that USP21 increases macropinocytosis by microtubule-affinity-regulating kinase 3 (MARK3), thus providing metabolic support after KRAS mutation extinction in PDAC cancer cells [51].”
From Targeting KRAS mutant cancers: from druggable therapy to drug resistance (2022) · cites this paper as [51]
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References 38 · Cited by 96
- Authors
- Hou, P., Ma, X., Zhang, Q., Wu, C.-J., Liao, W., Li, J., Wang, H., Zhao, J., Zhou, X., Guan, C., Ackroyd, J., Jiang, S., Zhang, J., Spring, D. J., Wang, Y. A., & DePinho, R. A.
- Affiliations
- The University of Texas MD Anderson Cancer Center (US)
- Princeton University (US)
- ORCID
- Venue
- Genes & Development
- Publisher
- Cold Spring Harbor Laboratory
- Published
- 2019-09-05
- Volume
- 33
- Issue
- 19-20
- Pages
- 1361-1366
- ISSN
- 0890-9369 (ISSN-L)
- 1549-5477
- PMC
- PMC6771391
- OpenAlex
- W2971482288
- Cited by
- 96
- References
- 38
- Citations by year
- 2026: 4 · 2025: 12 · 2024: 16 · 2023: 27 · 2022: 14 · 2021: 12 · 2020: 10 · 2018: 1
- Type
- posted content
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by-nc
- Locations
- Genes & Development (publishedVersion, cc-by-nc)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- HighWire Press Open Archive (submittedVersion)
- Funders
- Hirshberg Foundation for Pancreatic Cancer Research
- Cancer Center (CA016672)
- National Cancer Institute (P01 CA117969)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Wnt/β-catenin signaling in development and cancer
- Keywords
- USP21, deubiquitinase, pancreatic ductal adenocarcinoma, cancer stemness, Wnt signaling, TCF1, protein stabilization, oncogenes, cysteine protease, druggable targets
- MeSH terms
- Animals, Humans, Pancreatic Neoplasms, Neoplastic Stem Cells, Gene Expression Regulation, Neoplastic, Ubiquitin Thiolesterase, Cell Line, Tumor, Mice, T Cell Transcription Factor 1, Ubiquitination, Wnt Signaling Pathway
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