2. Academic Validation
  3. The Actin Histidine methyltransferase SETD3 is a CHD1 lysine di-methyltransferase

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

  • Cancer Lett. 2025 Oct 2:218073. doi: 10.1016/j.canlet.2025.218073.
Weilin Peng 1,  Christopher Wang 2,  Rui Yang 1,  Xiong Peng 1,  Zhenyu Zhao 1,  Boxue He 1,  Bei Qing 1,  Qidong Cai 1,  Wei Yin 1,  Yichuan Chen 3,  Fenglei Yu 1,  Xiang Wang 4,  Yongguang Tao 5
Affiliations

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.

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