ATR‐dependent ubiquitin‐specific protease 20 phosphorylation confers oxaliplatin and ferroptosis resistance
Abstract Oxaliplatin (OXA) resistance is a major clinic challenge in hepatocellular carcinoma (HCC). Ferroptosis is a kind of iron‐dependent cell death. Triggering ferroptosis is considered to restore sensitivity to chemotherapy. In the present study, we found that USP20 was overexpressed in OXA‐res...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2023-12-01
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| Series: | MedComm |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/mco2.463 |
| _version_ | 1827396502031433728 |
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| author | Jianing Tang Guo Long Desheng Xiao Shuang Liu Liang Xiao Ledu Zhou Yongguang Tao |
| author_facet | Jianing Tang Guo Long Desheng Xiao Shuang Liu Liang Xiao Ledu Zhou Yongguang Tao |
| author_sort | Jianing Tang |
| collection | DOAJ |
| description | Abstract Oxaliplatin (OXA) resistance is a major clinic challenge in hepatocellular carcinoma (HCC). Ferroptosis is a kind of iron‐dependent cell death. Triggering ferroptosis is considered to restore sensitivity to chemotherapy. In the present study, we found that USP20 was overexpressed in OXA‐resistant HCC cells. High expression of USP20 in HCC was associated with poor prognosis. USP20 contributes OXA resistance and suppress ferroptosis in HCC. Pharmacological inhibition or knockdown of USP20 triggered ferroptosis and increased the sensitivity of HCC cells to OXA both in vitro and in vivo. Coimmunoprecipitation results revealed that the UCH domain of USP20 interacted with the N terminal of SLC7A11. USP20 stabilized SLC7A11 via removing K48‐linked polyubiquitination of SLC7A11 protein at K30 and K37. Most importantly, DNA damage‐induced ATR activation was required for Ser132 and Ser368 phosphorylation of USP20. USP20 phosphorylation at Ser132 and Ser368 enhanced its stability and thus conferred OXA and ferroptosis resistance of HCC cells. Our study reveals a previously undiscovered association between OXA and ferroptosis and provides new insight into mechanisms regarding how DNA damage therapies always lead to therapeutic resistance. Therefore, targeting USP20 may mitigate the development of drug resistance and promote ferroptosis of HCC in patients receiving chemotherapy. |
| first_indexed | 2024-03-08T18:51:58Z |
| format | Article |
| id | doaj.art-5abb93a062e143fc9f79c0b3a6d4bfcf |
| institution | Directory Open Access Journal |
| issn | 2688-2663 |
| language | English |
| last_indexed | 2024-03-08T18:51:58Z |
| publishDate | 2023-12-01 |
| publisher | Wiley |
| record_format | Article |
| series | MedComm |
| spelling | doaj.art-5abb93a062e143fc9f79c0b3a6d4bfcf2023-12-28T16:52:34ZengWileyMedComm2688-26632023-12-0146n/an/a10.1002/mco2.463ATR‐dependent ubiquitin‐specific protease 20 phosphorylation confers oxaliplatin and ferroptosis resistanceJianing Tang0Guo Long1Desheng Xiao2Shuang Liu3Liang Xiao4Ledu Zhou5Yongguang Tao6Department of Liver Surgery Xiangya Hospital Central South University Changsha Hunan ChinaDepartment of Liver Surgery Xiangya Hospital Central South University Changsha Hunan ChinaDepartment of Pathology Xiangya Hospital Central South University Changsha Hunan ChinaDepartment of Oncology Institute of Medical Sciences National Clinical Research Center for Geriatric Disorders Xiangya Hospital Central South University Changsha Hunan ChinaDepartment of Liver Surgery Xiangya Hospital Central South University Changsha Hunan ChinaDepartment of Liver Surgery Xiangya Hospital Central South University Changsha Hunan ChinaDepartment of Pathology Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education) Xiangya Hospital Central South University Hunan ChinaAbstract Oxaliplatin (OXA) resistance is a major clinic challenge in hepatocellular carcinoma (HCC). Ferroptosis is a kind of iron‐dependent cell death. Triggering ferroptosis is considered to restore sensitivity to chemotherapy. In the present study, we found that USP20 was overexpressed in OXA‐resistant HCC cells. High expression of USP20 in HCC was associated with poor prognosis. USP20 contributes OXA resistance and suppress ferroptosis in HCC. Pharmacological inhibition or knockdown of USP20 triggered ferroptosis and increased the sensitivity of HCC cells to OXA both in vitro and in vivo. Coimmunoprecipitation results revealed that the UCH domain of USP20 interacted with the N terminal of SLC7A11. USP20 stabilized SLC7A11 via removing K48‐linked polyubiquitination of SLC7A11 protein at K30 and K37. Most importantly, DNA damage‐induced ATR activation was required for Ser132 and Ser368 phosphorylation of USP20. USP20 phosphorylation at Ser132 and Ser368 enhanced its stability and thus conferred OXA and ferroptosis resistance of HCC cells. Our study reveals a previously undiscovered association between OXA and ferroptosis and provides new insight into mechanisms regarding how DNA damage therapies always lead to therapeutic resistance. Therefore, targeting USP20 may mitigate the development of drug resistance and promote ferroptosis of HCC in patients receiving chemotherapy.https://doi.org/10.1002/mco2.463chemoresistanceferroptosishepatocellular carcinomasolute carrier family 7 member 11ubiquitin‐specific peptidase 20 |
| spellingShingle | Jianing Tang Guo Long Desheng Xiao Shuang Liu Liang Xiao Ledu Zhou Yongguang Tao ATR‐dependent ubiquitin‐specific protease 20 phosphorylation confers oxaliplatin and ferroptosis resistance MedComm chemoresistance ferroptosis hepatocellular carcinoma solute carrier family 7 member 11 ubiquitin‐specific peptidase 20 |
| title | ATR‐dependent ubiquitin‐specific protease 20 phosphorylation confers oxaliplatin and ferroptosis resistance |
| title_full | ATR‐dependent ubiquitin‐specific protease 20 phosphorylation confers oxaliplatin and ferroptosis resistance |
| title_fullStr | ATR‐dependent ubiquitin‐specific protease 20 phosphorylation confers oxaliplatin and ferroptosis resistance |
| title_full_unstemmed | ATR‐dependent ubiquitin‐specific protease 20 phosphorylation confers oxaliplatin and ferroptosis resistance |
| title_short | ATR‐dependent ubiquitin‐specific protease 20 phosphorylation confers oxaliplatin and ferroptosis resistance |
| title_sort | atr dependent ubiquitin specific protease 20 phosphorylation confers oxaliplatin and ferroptosis resistance |
| topic | chemoresistance ferroptosis hepatocellular carcinoma solute carrier family 7 member 11 ubiquitin‐specific peptidase 20 |
| url | https://doi.org/10.1002/mco2.463 |
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