2. Academic Validation
  3. METTL21A promotes hepatocellular carcinoma progression via methylating and stabilizing BAG3

METTL21A promotes hepatocellular carcinoma progression via methylating and stabilizing BAG3

  • NPJ Precis Oncol. 2025 Jul 10;9(1):234. doi: 10.1038/s41698-025-01021-5.
Ping Zhan # 1,  Yizhe Cheng # 1,  Yingcan Wu 1,  Jing Lu 1,  Jing Wen 2,  Xiaoqin Chi 1,  Changhong Luo 1,  Yiwei Peng 2,  Xijun Chen 3 4,  Fuqiang Wang 5,  Zhenyu Yin 6,  Chengrong Xie 7
Affiliations

Affiliations

  • 1 Fujian Provincial Key Laboratory of Chronic Liver Disease and Hepatocellular Carcinoma, Xiamen Translational Medical Key Laboratory of Digestive System Tumor, Zhongshan Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China.
  • 2 Department of Hepatobiliary Surgery, Xiamen Key Laboratory of Liver Diseases, Xiamen Hospital of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Xiamen, China.
  • 3 Fujian Provincial Key Laboratory of Chronic Liver Disease and Hepatocellular Carcinoma, Xiamen Translational Medical Key Laboratory of Digestive System Tumor, Zhongshan Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China. jpltg@163.com.
  • 4 Department of Hepatobiliary Surgery, Xiamen Key Laboratory of Liver Diseases, Xiamen Hospital of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Xiamen, China. jpltg@163.com.
  • 5 Fujian Provincial Key Laboratory of Chronic Liver Disease and Hepatocellular Carcinoma, Xiamen Translational Medical Key Laboratory of Digestive System Tumor, Zhongshan Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China. wangfq@xmu.edu.cn.
  • 6 Fujian Provincial Key Laboratory of Chronic Liver Disease and Hepatocellular Carcinoma, Xiamen Translational Medical Key Laboratory of Digestive System Tumor, Zhongshan Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China. yinzy@xmu.edu.cn.
  • 7 Fujian Provincial Key Laboratory of Chronic Liver Disease and Hepatocellular Carcinoma, Xiamen Translational Medical Key Laboratory of Digestive System Tumor, Zhongshan Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China. xiecr@xmu.edu.cn.
  • # Contributed equally.
PMID: 40640484 DOI: 10.1038/s41698-025-01021-5
Abstract

Protein methyltransferases regulate diverse physiological and pathological processes through histone and non-histone substrate methylation. While the role of histone methyltransferases in tumorigenesis is well-established, the contribution of non-histone methyltransferases, particularly Methyltransferase 21A (METTL21A), to hepatocellular carcinoma (HCC) progression remains poorly characterized. Here, we report that METTL21A is significantly upregulated in HCC tissues and associated with poor clinical prognosis. Transcriptional activation by CCCTC-binding factor (CTCF) was identified as a key driver of METTL21A overexpression. Functional studies demonstrated that METTL21A promotes HCC growth and metastasis in both in vitro and in vivo models. Mechanistically, METTL21A mediates methylation of Bcl-2-associated athanogene-3 (BAG3), thereby inhibiting its ubiquitination and subsequent degradation. We further identified Tripartite motif containing 21 (TRIM21) as the E3 Ligase responsible for BAG3 ubiquitination and found that METTL21A disrupts the TRIM21-BAG3 interaction. Notably, we discovered that the natural compound sophoricoside (Sop) acts as a METTL21A inhibitor and exhibits potent anti-HCC activity. Our study not only elucidates the oncogenic role and molecular mechanism of METTL21A in HCC progression but also highlights its therapeutic potential as a novel drug target for HCC treatment.

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