METTL9, short for Methytransferase-like proteins 9, functions as a methyltransferase. It mediates the formation of 1-methylhistidine in mammalian proteomes, a post-translational modification crucial for regulating protein function [3]. METTL9-catalyzed methylation requires a His-x-His (HxH) motif in substrates, and it enhances mitochondrial respiration via Complex I [3]. It may also be involved in innate immune response to bacterial and fungal infections by methylating the proinflammatory protein S100A9 [4].

In hepatocellular carcinoma (HCC), METTL9 acts as an oncogene. Its high expression is associated with poor survival outcomes. Knockdown of METTL9 significantly inhibits HCC cell viability, migration, and invasion both in vitro and in vivo, while overexpression leads to stronger cell proliferation and migration abilities. Mechanistically, METTL9 knockdown reduces the expression of SLC7A11, a ferroptosis suppressor, promoting ferroptosis and impeding HCC progression. Targeting METTL9 can restrain the growth of HCC patient-derived xenograft (PDX) [1]. In scirrhous gastric cancers, elevated METTL9 is associated with peritoneal dissemination. Stable knockdown of METTL9 in metastatic cells from scirrhous gastric cancer patients significantly inhibits migration and invasion, and METTL9 knockdown also reduces mitochondrial Complex I activity [2].

In conclusion, METTL9 is a key methyltransferase involved in regulating protein function through histidine methylation. Its dysregulation is associated with the progression of certain cancers, such as HCC and scirrhous gastric cancers. Studies using knockdown models have revealed its oncogenic roles in these cancer types, providing potential therapeutic targets for cancer treatment.

References:

1. Bi, Fangfang, Qiu, Yuxiong, Wu, Zongfeng, Niu, Yi, Qiu, Jiliang. 2023. METTL9-SLC7A11 axis promotes hepatocellular carcinoma progression through ferroptosis inhibition. In Cell death discovery, 9, 428. doi:10.1038/s41420-023-01723-4. https://pubmed.ncbi.nlm.nih.gov/38017014/

2. Hara, Toshifumi, Tominaga, Yuuki, Ueda, Koji, Yanagihara, Kazuyoshi, Takei, Yoshifumi. 2022. Elevated METTL9 is associated with peritoneal dissemination in human scirrhous gastric cancers. In Biochemistry and biophysics reports, 30, 101255. doi:10.1016/j.bbrep.2022.101255. https://pubmed.ncbi.nlm.nih.gov/35402738/

3. Davydova, Erna, Shimazu, Tadahiro, Schuhmacher, Maren Kirstin, Shinkai, Yoichi, Falnes, Pål Ø. 2021. The methyltransferase METTL9 mediates pervasive 1-methylhistidine modification in mammalian proteomes. In Nature communications, 12, 891. doi:10.1038/s41467-020-20670-7. https://pubmed.ncbi.nlm.nih.gov/33563959/

4. Daitoku, Hiroaki, Someya, Momoka, Kako, Koichiro, Akimoto, Yuto, Fukamizu, Akiyoshi. 2021. siRNA screening identifies METTL9 as a histidine Nπ-methyltransferase that targets the proinflammatory protein S100A9. In The Journal of biological chemistry, 297, 101230. doi:10.1016/j.jbc.2021.101230. https://pubmed.ncbi.nlm.nih.gov/34562450/