Researchers found an association between methyltransferases like 3 (METTL3) expression and poor prognosis in patients with intrahepatic cholangiocarcinoma (iCCA), as published in Oncogene. METTL3 promoted iCCA progression, suggesting that it might be a potential therapeutic target for the disease.

“Mechanistically, we found that [tri-methylation of lysine 4 on histone 3] activation-driven transcription is the reason for the dysregulation of METTL3 in [iCCA],” the authors wrote.

MTTL3 was found to be upregulated in 3 different iCCA datasets. Immunohistochemistry analysis of paraffin-embedded specimens of 96 patients with iCCA revealed that MTTL3 expression was positively correlated with tumor size and tumor, node, metastasis stage.


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Moreover, patients with high METTL3 expression had poorer disease-free survival and overall survival (OS). These results were further supported by multivariate regression analysis, which highlighted METTL3 expression as an independent predictor of OS in patients with iCCA.

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Knockdown of MTTL3 inhibited the proliferation of iCCA cells, while its overexpression led to opposite effects and drove iCCA progression. Accordingly, treating cells with STM2457, a selective METTL3 inhibitor, also inhibited proliferation, invasion, and migration in a dose-dependent manner, while promoting apoptosis and cell cycle arrest at S-phase.

At the molecular level, METTL3 downregulated the expression of the interferon-induced protein with tetratricopeptide repeats 2 (IFIT2). IFIT2 is involved in the innate immune response, being a direct response target of type-I interferons. It has been proposed as a tumor suppressor in several cancers.

MTTL3-mediated downregulation of IFIT2 was shown to be dependent on YTH domain-containing family protein 2 (YTHDF2), which is known to induce the degradation of mRNAs by reading N6-methyadenosine modification sites.

Reference

Xu Q-C, Tien Y-C, Shi Y-H, et al. METTL3 promotes intrahepatic cholangiocarcinoma progression by regulating IFIT2 expression in an m6A-YTHDF2-dependent manner. Oncogene. Published online January 29, 2022. doi:10.1038/s41388-022-02185-1