METTL21A promotes hepatocellular carcinoma progression via methylating and stabilizing BAG3.

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.