2. Academic Validation
  3. Regulation of KDM5C stability and enhancer reprogramming in breast cancer

Regulation of KDM5C stability and enhancer reprogramming in breast cancer

  • Cell Death Dis. 2022 Oct 3;13(10):843. doi: 10.1038/s41419-022-05296-5.
Qiong Xiao 1,  Chen-Yu Wang 1,  Chuan Gao 1,  Ji-Dong Chen 1,  Jing-Jing Chen 1,  Zhen Wang 1,  Lin-Gao Ju 2,  Shan-Bo Tang 1,  Jie Yao 1,  Feng Li 3,  Lian-Yun Li 1,  Min Wu 4
Affiliations

Affiliations

  • 1 Frontier Science Center for Immunology and Metabolism, Hubei Key Laboratory of Cell Homeostasis, Hubei Key Laboratory of Developmentally Originated Disease, College of Life Sciences, Renmin Hospital of Wuhan University, Wuhan University, Wuhan, 430072, Hubei, China.
  • 2 Department of Biological Repositories, Zhongnan Hospital of Wuhan University, Wuhan, 430071, Hubei, China.
  • 3 Department of Medical Genetics, School of Basic Medical Sciences, Wuhan University, 430071, Wuhan, China.
  • 4 Frontier Science Center for Immunology and Metabolism, Hubei Key Laboratory of Cell Homeostasis, Hubei Key Laboratory of Developmentally Originated Disease, College of Life Sciences, Renmin Hospital of Wuhan University, Wuhan University, Wuhan, 430072, Hubei, China. [email protected].
PMID: 36192394 DOI: 10.1038/s41419-022-05296-5
Abstract

Abnormality of enhancer regulation has emerged as one of the critical features for Cancer cells. KDM5C is a histone H3K4 demethylase and frequently mutated in several types of Cancer. It is critical for H3K4me3 and activity of enhancers, but its regulatory mechanisms remain elusive. Here, we identify TRIM11 as one ubiquitin E3 ligase for KDM5C. TRIM11 interacts with KDM5C, catalyzes K48-linked ubiquitin chain on KDM5C, and promotes KDM5C degradation through Proteasome. TRIM11 deficiency in an animal model represses the growth of breast tumor and stabilizes KDM5C. In breast Cancer patient tissues, TRIM11 is highly expressed and KDM5C is lower expressed, and their expression is negatively correlated. Mechanistically, TRIM11 regulates the enhancer activity of genes involved in cell migration and immune response by targeting KDM5C. TRIM11 and KDM5C regulate MCAM expression and cell migration through targeting H3K4me3 on MCAM enhancer. Taken together, our study reveals novel mechanisms for enhancer regulation during breast Cancer tumorigenesis and development.

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