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Usp11 deletion reduces E-cadherin and increases DNA damage in mammary epithelial cells, while WT USP11 restores luminal differentiation and suppresses tumor growth via deubiquitinating E-cadherin at K738.",{"@graph":14,"@context":65},[15,34,56],{"@type":16,"itemListElement":17},"BreadcrumbList",[18,23,27,31],{"item":19,"name":20,"@type":21,"position":22},"https://docshare.wps.com","Home","ListItem",1,{"item":24,"name":25,"@type":21,"position":26},"https://docshare.wps.com/document/","Document",2,{"item":28,"name":29,"@type":21,"position":30},"https://docshare.wps.com/document/research-report/","Research & 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cells to suppress breast cancer  \nReceived for publication, February 4, 2024, and in revised form, August 1, 2024 Published, Papers in Press, September 11, 2024, [https://doi.org/10.1016/j.jbc.2024.107768](https://doi.org/10.1016/j.jbc.2024.107768)  \nTao Qian 1, Feng Bai 1,2, Shiwen Zhang 1, Yuping Xu 1, Yuchan Wang3, Shuping Yuan4, Xiong Liu 1, Yaru Du 1, Bin Peng4, Wei-Guo Zhu5, Xingzhi Xu4, *, and Xin-Hai Pei 1,6, *  \nFrom the 1Guangdong Provincial Key Laboratory of Regional Immunity and Diseases, International Cancer Center, Marshall  \nLaboratory of Biomedical Engineering, General Hospital, Shenzhen University, School, Shenzhen University, Shenzhen,  \nThe First Affiliated Hospital, Shenzhen University Medical School, Shenzhen University Shenzhen, Guangdong, China; 2Department of Pathology, Shenzhen University Medical Guangdong, China; 3Gansu Dian Medical Laboratory, Lanzhou, China; 4Guangdong Key  \nLaboratory for Genome Stability & Disease Prevention and International Cancer Center, Shenzhen University Medical School, Shenzhen University, Shenzhen, Guangdong, China; 5Department of Biochemistry and Molecular Biology, International Cancer Center, Shenzhen University Medical School, Shenzhen University, Shenzhen, Guangdong, China; 6Department of Anatomy and Histology, Shenzhen University Medical School, Shenzhen University, Shenzhen, Guangdong, China  \nReviewed by members of the JBC Editorial Board. Edited by Paul Shapiro  \nBasal-like breast cancer may originate from luminal epithelial or cancerous cells. Inadequately repaired DNA damage impairs luminal differentiation and promotes aberrant luminalto basal trans-differentiation in mammary epithelial cells (MECs). Ubiquitin-specific peptidase 11 (USP11), a deubiquitinase, plays a critical role in DNA damage repair. The role of USP11 in controlling mammary cell differentiation and tumorigenesis remains poorly understood. We generated Usp11 knockout mice and breast cancer cell lines expressing wild-type (WT) and mutant forms of USP11. By using these mutant mice, cell lines, and human USP11-deficient and-proficient breast cancer tissues, we tested how USP11 controls mammary cell fate. We generated Usp11 knock-out mice and found that deletion of Usp11 reduced the expression of E-cadherin and promoted DNA damage in MECs. Overexpression of WT USP11, but not a deubiquitinase-inactive mutant form of USP11, promoted luminal differentiation, enhanced DNA damage repair, and suppressed tumorigenesis in mice. Mechanistically, we found that USP11 enhanced the protein expression of E-cadherin dependent on its deubiquitinase activity and that USP11 deubiquitinated E-cadherin at K738. We discovered that USP11 is bound to E-cadherin through its C-terminal region. In human breast cancers, expression of USP11 was positively correlated with that of Ecadherin, and high USP11 predicted better recurrence-free survival. Our findings provide compelling genetic and biochemical evidence that USP11 not only promotes DNA damage repair but also deubiquitinates E-cadherin and maintains the luminal feature of mammary tumor cells, thereby suppressing luminal breast cancer.  \nBreast cancer has been the most frequently diagnosed typeof cancer since 2020, and it is also the second-leading cause of  \n* For correspondence: Xingzhi Xu, [xingzhi.xu@szu.edu.cn](xingzhi.xu@szu.edu.cn); Xin-Hai Pei, [peixinhai@szu.edu.cn](peixinhai@szu.edu.cn).  \ndeath in women (1). Breast cancer comprises of, among others, two main subtypes: estrogen receptor (ER)-positive luminaland ER-negative basal-like. Basal-like breast cancers (BLBCs) are highly invasive, poorly differentiated, and contain several distinct cell types such as cells that express luminal and basal biomarkers (2). We and others have demonstrated that some of the BLBCs originate from luminal epithelial or cancerous cells (3–7). Luminal breast cancers account for more than tw","cbCaivCDf2OlLNBf","https://ap.wps.com/l/cbCaivCDf2OlLNBf","pdf",3781141,15,"English","# Background\n## Mammary cell differentiation and breast cancer subtypes\n# Experimental approach\n## Mouse and cell models\n## Human tissue correlation\n# Results\n## USP11 loss promotes DNA damage and reduces E-cadherin\n## USP11 deubiquitinates E-cadherin at K738\n# Conclusions\n## USP11 maintains luminal fate to suppress tumorigenesis","[{\"question\":\"How does USP11 regulate E-cadherin mechanistically?\",\"answer\":\"USP11 enhances E-cadherin protein expression through its deubiquitinase activity and deubiquitinates E-cadherin at lysine K738.\"}]","USP11 deubiquitinates E-cadherin and maintains the luminal fate of mammary tumor cells to suppress breast cancer | PDF",1789983047,38]