Methylations are among the most prevalent RNA modifications and multiple METTL proteins have been implicated in different types of cancers. In a recent publication in Science Advances, a team of researchers from the Helmholtz-Zentrum München and colleagues discovered the impact of the RNA-modifying enzyme METTL6 as a potential new oncogene.
DNA and histone modifications control gene expression - this is well established - but there are new players. The epitranscriptome, consisting of a set of covalent modifications to RNA, is a crucial in addition. While genetic mutations have a direct effect on the DNA sequence, epigenetic or epitranscriptomic alterations do not affect the DNA sequence directly. In a normal cell, these mechanisms ensure that only the proteins required for the cellular function and identity are produced. In a cancer cells, however, these mechanisms can be dysregulated.
In this study the scientists combined in vitro and in vivo screens to test 78 potential methyltransferases for their roles in hepatocellular carcinoma (HCC) cell proliferation and identified methyltransferase-like protein 6 (METTL6) as a crucial regulator of tumor cell growth. Deletion of Mettl6 in mouse stem cells results in changes in ribosome occupancy and RNA levels, as well as impaired pluripotency. In line with the finding that loss of METTL6 inhibits liver cancer cell proliferation including impaired colony formation capacity and capacity for anchorage-independent growth, low expression of METTL6 correlates with increased survival of patients with HCC.
To investigate the function of METTL6 in vivo, METTL6 deficient mice were generated and systemic phenotyping revealed that adult Mettl6 KO mice did not display overt morphological defects. Male KO mice showed a significant reduction in body weight over time and when tested for glucose tolerance, KO mice showed an impaired glucose response. Despite that, Mettl6 KO mice displayed a reduced metabolic rate.
METTL6 could be a potential therapeutic target for anti-proliferative cancer drugs, but can also to help to understand the links between cancer and metabolic dysfunction. Given the recent success in identifying selective and potent small-molecule inhibitors of methyltransferases, RNA methyltransferases such as METTL6 could thus represent novel therapeutic targets for antiproliferative cancer drugs.
Ignatova VV, Kaiser S, Ho JSY, Bing X, Stolz P, Tan YX, Lee CL, Gay FPH, Lastres PR, Gerlini R, Rathkolb B, Aguilar-Pimentel A, Sanz-Moreno A, Klein-Rodewald T, Calzada-Wack J, Ibragimov E, Valenta M, Lukauskas S, Pavesi A, Marschall S, Leuchtenberger S, Fuchs H, Gailus-Durner V, de Angelis MH, Bultmann S, Rando OJ, Guccione E, Kellner SM, Schneider R. Sci Adv. 2020 Aug 26;6(35):eaaz4551. doi: 10.1126/sciadv.aaz4551. eCollection 2020 Aug.
METTL6 is a tRNA m3C methyltransferase that regulates pluripotency and tumor cell growth.