2. Academic Validation
  3. USP11 deubiquitinates E-cadherin and maintains the luminal fate of mammary tumor cells to suppress breast cancer

USP11 deubiquitinates E-cadherin and maintains the luminal fate of mammary tumor cells to suppress breast cancer

  • J Biol Chem. 2024 Oct;300(10):107768. doi: 10.1016/j.jbc.2024.107768.
Tao Qian 1,  Feng Bai 2,  Shiwen Zhang 1,  Yuping Xu 1,  Yuchan Wang 3,  Shuping Yuan 4,  Xiong Liu 1,  Yaru Du 1,  Bin Peng 4,  Wei-Guo Zhu 5,  Xingzhi Xu 6,  Xin-Hai Pei 7
Affiliations

Affiliations

  • 1 Guangdong Provincial Key Laboratory of Regional Immunity and Diseases, International Cancer Center, Marshall Laboratory of Biomedical Engineering, The First Affiliated Hospital, Shenzhen University Medical School, Shenzhen University General Hospital, Shenzhen University, Shenzhen, Guangdong, China.
  • 2 Guangdong Provincial Key Laboratory of Regional Immunity and Diseases, International Cancer Center, Marshall Laboratory of Biomedical Engineering, The First Affiliated Hospital, Shenzhen University Medical School, Shenzhen University General Hospital, Shenzhen University, Shenzhen, Guangdong, China; Department of Pathology, Shenzhen University Medical School, Shenzhen University, Shenzhen, Guangdong, China.
  • 3 Gansu Dian Medical Laboratory, Lanzhou, China.
  • 4 Guangdong Key Laboratory for Genome Stability & Disease Prevention and International Cancer Center, Shenzhen University Medical School, Shenzhen University, Shenzhen, Guangdong, China.
  • 5 Department of Biochemistry and Molecular Biology, International Cancer Center, Shenzhen University Medical School, Shenzhen University, Shenzhen, Guangdong, China.
  • 6 Guangdong Key Laboratory for Genome Stability & Disease Prevention and International Cancer Center, Shenzhen University Medical School, Shenzhen University, Shenzhen, Guangdong, China. Electronic address: xingzhi.xu@szu.edu.cn.
  • 7 Guangdong Provincial Key Laboratory of Regional Immunity and Diseases, International Cancer Center, Marshall Laboratory of Biomedical Engineering, The First Affiliated Hospital, Shenzhen University Medical School, Shenzhen University General Hospital, Shenzhen University, Shenzhen, Guangdong, China; Department of Anatomy and Histology, Shenzhen University Medical School, Shenzhen University, Shenzhen, Guangdong, China. Electronic address: peixinhai@szu.edu.cn.
PMID: 39270819 DOI: 10.1016/j.jbc.2024.107768
Abstract

Basal-like breast Cancer may originate from luminal epithelial or cancerous cells. Inadequately repaired DNA damage impairs luminal differentiation and promotes aberrant luminal to 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 E-cadherin, 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.

Keywords

E-cadherin; USP11; breast cancer; deubiquitination; luminal fate.

Figures
Products
嗨！很高兴为您提供帮助！

尊敬的 MCE 客户您好，
请您选择所在区域，我们将转接对应客服为您服务！

热门区域

A

B

C

F

G

H

J

L

N

Q

S

T

X

Y

Z

热 A B C F G H J L N Q S T X Y Z