MT2A facilitates the malignant progression of clear cell renal cell carcinoma by activating the TFAP2A/YAP axis via histone lactylation.

BACKGROUND: Clear cell Renal cell carcinoma (ccRCC) represents the most common malignant tumor of the kidney. Metallothionein 2A (MT2A) is abnormally expressed in various cancers, but its functional role and underlying mechanism in RCC remain to be elucidated.

METHODS: The expression of MT2A in RCC and its adjacent tissues was analyzed using the public TCGA and GEO databases. The effects of MT2A on cell proliferation, migration and invasion were investigated by using CCK-8, Transwell, and wound healing assays. Potential downstream targets and pathways were screened by transcriptomic and metabolomic sequencing. The regulatory mechanisms were further validated via qRT-PCR, Western blotting, ChIP, immunohistochemistry, luciferase reporter assays, and CUT&Tag. Moreover, the in vivo function of MT2A was investigated using a nude mouse xenograft tumor model.

RESULTS: MT2A was significantly upregulated in ccRCC and correlated with clinical stage and overall survival. MT2A enhanced ccRCC metastatic potential and epithelial-mesenchymal transition, with a moderate, late-onset effect on cell proliferation, via the TFAP2A/YAP axis. MT2A was shown to enhance lactic acid accumulation and H3K18 lactylation. Further studies confirmed that MT2A contributed to TFAP2A transcription via HBO1-mediated H3K18 lactylation. Consistently, MT2A knockdown in vivo enhanced the tumor-suppressing effect of sorafenib.

CONCLUSIONS: MT2A could promote the malignant progression of ccRCC through the TFAP2A/YAP axis, which is controlled by HBO1-mediated H3K18 lactylation. Targeting MT2A effectively inhibits tumor growth and enhances the efficacy of sorafenib, providing a novel potential therapeutic target for ccRCC.