Regulation of KDM5C stability and enhancer reprogramming in breast cancer

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 identif...

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Bibliographic Details
Published in:Cell death & disease 2022-10, Vol.13 (10), p.843-13, Article 843
Main Authors: Xiao, Qiong, Wang, Chen-Yu, Gao, Chuan, Chen, Ji-Dong, Chen, Jing-Jing, Wang, Zhen, Ju, Lin-Gao, Tang, Shan-Bo, Yao, Jie, Li, Feng, Li, Lian-Yun, Wu, Min
Format: Article
Language:English
Subjects:
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Animal models
Animals
Antibodies
Biochemistry
Biomedical and Life Sciences
Breast cancer
Carcinogenesis - genetics
Cell adhesion & migration
Cell Biology
Cell Culture
Cell Line, Tumor
Cell migration
Enhancers
Histone Demethylases - genetics
Histone Demethylases - metabolism
Histones
Histones - genetics
Histones - metabolism
Immune response
Immunology
Life Sciences
Neoplasms
Proteasome Endopeptidase Complex - metabolism
Proteasomes
Tumorigenesis
Ubiquitin
Ubiquitin-protein ligase
Ubiquitin-Protein Ligases - genetics
Ubiquitin-Protein Ligases - metabolism
Ubiquitins - metabolism
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Summary: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.
ISSN:2041-4889
2041-4889
DOI:10.1038/s41419-022-05296-5