The Actin Histidine methyltransferase SETD3 is a CHD1 lysine di-methyltransferase

Weilin Peng; Christopher Wang; Rui Yang; Xiong Peng; Zhenyu Zhao; Boxue He; Bei Qing; Qidong Cai; Wei Yin; Yichuan Chen; Fenglei Yu; Xiang Wang; Yongguang Tao

doi:10.1016/j.canlet.2025.218073

The Actin Histidine methyltransferase SETD3 is a CHD1 lysine di-methyltransferase

Cancer Lett. 2025 Dec 1:634:218073. doi: 10.1016/j.canlet.2025.218073. Epub 2025 Oct 2.

Authors

Weilin Peng¹, Christopher Wang², Rui Yang¹, Xiong Peng¹, Zhenyu Zhao¹, Boxue He¹, Bei Qing¹, Qidong Cai¹, Wei Yin¹, Yichuan Chen³, Fenglei Yu¹, Xiang Wang⁴, Yongguang Tao⁵

Affiliations

¹ Department of Thoracic Surgery, the Second Xiangya Hospital of Central South University, 410011, Changsha, Hunan, China; Hunan Key Laboratory of Early Diagnosis and Precise Treatment of Lung Cancer, the Second Xiangya Hospital of Central South University, 410011, Changsha, Hunan, China.
² Department of Thoracic Surgery, the Second Xiangya Hospital of Central South University, 410011, Changsha, Hunan, China.
³ Department of Cardiovascular Surgery, The Second Xiangya Hospital, Central South University, Changsha, China.
⁴ Department of Thoracic Surgery, the Second Xiangya Hospital of Central South University, 410011, Changsha, Hunan, China; Hunan Key Laboratory of Early Diagnosis and Precise Treatment of Lung Cancer, the Second Xiangya Hospital of Central South University, 410011, Changsha, Hunan, China. Electronic address: wangxiang@csu.edu.cn.
⁵ Department of Thoracic Surgery, the Second Xiangya Hospital of Central South University, 410011, Changsha, Hunan, China; Hunan Key Laboratory of Early Diagnosis and Precise Treatment of Lung Cancer, the Second Xiangya Hospital of Central South University, 410011, Changsha, Hunan, China; Department of Pathology, School of Basic Medicine and Xiangya Hospital, Central South University, 410008, Changsha, Hunan, China; NHC Key Laboratory of Carcinogenesis, Cancer Research Institute and School of Basic Medicine, Central South University, Changsha, Hunan, 410078, China. Electronic address: taoyong@csu.edu.cn.

PMID: 41045985
DOI: 10.1016/j.canlet.2025.218073

Abstract

Protein methylation is a widespread posttranslational modification that primarily targets lysine, arginine, and histidine residues. Aberrant protein methylation has been implicated in tumorigenesis, although the specific role of SETD3, a histidine methyltransferase, in cancer remains poorly understood. In this study, we identify CHD1 as a novel substrate of SETD3, which dimethylates CHD1 at lysine 209 (K209). Dimethylation at this site enhances CHD1 protein stability by reducing its ubiquitination. Furthermore, SETD3 mediates methylation of CHD1 to enhance H3K4me3 epigenetic marks and promote transcriptional activation of TNF-NFκB pathway genes. Collectively, our findings establish CHD1 as a new substrate for SETD3 and reveal a mechanism by which SETD3-mediated dimethylation of CHD1 at K209 promotes tumor progression.

Keywords: Lysine methylation; Protein stability; TNF–NFκB pathway; Ubiquitination.

MeSH terms

DNA-Binding Proteins* / genetics
DNA-Binding Proteins* / metabolism
Epigenesis, Genetic
HEK293 Cells
Histone Methyltransferases
Histone-Lysine N-Methyltransferase* / genetics
Histone-Lysine N-Methyltransferase* / metabolism
Histones / metabolism
Humans
Lysine / metabolism
Methylation
NF-kappa B / metabolism
Protein Processing, Post-Translational
Signal Transduction
Ubiquitination

Substances

Histone-Lysine N-Methyltransferase
SETD3 protein, human
DNA-Binding Proteins
Histones
Lysine
NF-kappa B
Histone Methyltransferases