Zhan Ping, Cheng Yizhe, Wu Yingcan, Lu Jing, Wen Jing, Chi Xiaoqin, Luo Changhong, Peng Yiwei, Chen Xijun, Wang Fuqiang, Yin Zhenyu, Xie Chengrong
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.
Department of Hepatobiliary Surgery, Xiamen Key Laboratory of Liver Diseases, Xiamen Hospital of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Xiamen, China.
NPJ Precis Oncol. 2025 Jul 10;9(1):234. doi: 10.1038/s41698-025-01021-5.
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.
蛋白质甲基转移酶通过组蛋白和非组蛋白底物甲基化来调节多种生理和病理过程。虽然组蛋白甲基转移酶在肿瘤发生中的作用已得到充分证实，但非组蛋白甲基转移酶，特别是甲基转移酶21A（METTL21A）对肝细胞癌（HCC）进展的贡献仍知之甚少。在此，我们报告METTL21A在HCC组织中显著上调，并与不良临床预后相关。CCCTC结合因子（CTCF）的转录激活被确定为METTL21A过表达的关键驱动因素。功能研究表明，METTL21A在体外和体内模型中均促进HCC的生长和转移。机制上，METTL21A介导Bcl-2相关抗凋亡基因3（BAG3）的甲基化，从而抑制其泛素化及随后的降解。我们进一步确定含三联基序蛋白21（TRIM21）为负责BAG3泛素化的E3连接酶，并发现METTL21A破坏TRIM21与BAG3的相互作用。值得注意的是，我们发现天然化合物槐角苷（Sop）作为一种METTL21A抑制剂，具有强大的抗HCC活性。我们的研究不仅阐明了METTL21A在HCC进展中的致癌作用和分子机制，还突出了其作为HCC治疗新药物靶点的治疗潜力。
