USP32 confers cancer cell resistance to YM155 via promoting ER-associated degradation of solute carrier protein SLC35F2open access
- Authors
- Chandrasekaran, Arun Pandian; Kaushal, Kamini; Park, Chang-Hwan; Kim, Kye-Seong; Ramakrishna, Suresh
- Issue Date
- Sep-2021
- Publisher
- Ivyspring International Publisher
- Keywords
- Cell apoptosis; DNA damage; Dose response; Drug transport-cargo; Human tumor tissues
- Citation
- Theranostics, v.11, no.20, pp.9752 - 9771
- Indexed
- SCIE
SCOPUS
- Journal Title
- Theranostics
- Volume
- 11
- Number
- 20
- Start Page
- 9752
- End Page
- 9771
- URI
- https://scholarworks.bwise.kr/hanyang/handle/2021.sw.hanyang/140968
- DOI
- 10.7150/THNO.63806
- ISSN
- 1838-7640
- Abstract
- Background: The most commonly preferred chemotherapeutic agents to treat cancers are small-molecule drugs. However, the differential sensitivity of various cancer cells to small molecules and untargeted delivery narrow the range of potential therapeutic applications. The mechanisms responsible for drug resistance in a variety of cancer cells are also largely unknown. Several deubiquitinating enzymes (DUBs) are the main determinants of drug resistance in cancer cells. Methods: We used CRISPR-Cas9 to perform genome-scale knockout of the entire set of genes encoding ubiquitin-specific proteases (USPs) and systematically screened for DUBs resistant to the clinically evaluated anticancer compound YM155. A series of in vitro and in vivo experiments were conducted to reveal the relationship between USP32 and SLC35F2 on YM155-mediated DNA damage in cancer cells. Results: CRISPR-based dual-screening method identified USP32 as a novel DUB that governs resistance for uptake of YM155 by destabilizing protein levels of SLC35F2, a solute-carrier protein essential for the uptake of YM155. The expression of USP32 and SLC35F2 was negatively correlated across a panel of tested cancer cell lines. YM155-resistant cancer cells in particular exhibited elevated expression of USP32 and low expression of SLC35F2. Conclusion: Collectively, our DUB-screening strategy revealed a resistance mechanism governed by USP32 associated with YM155 resistance in breast cancers, one that presents an attractive molecular target for anti-cancer therapies. Targeted genome knockout verified that USP32 is the main determinant of SLC35F2 protein stability in vitro and in vivo, suggesting a novel way to treat tumors resistant to small-molecule drugs.
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