METTL5, the N6-adenosine methyltransferase 5, is an enzyme responsible for 18S rRNA m6A modification [3]. This modification is crucial as it impacts ribosome synthesis and translation, thus influencing various biological processes such as cell differentiation, development, metabolism, and disease occurrence [4]. It has been associated with multiple pathways including the Wnt signaling pathway and those related to glucose, sphingomyelin, and fatty acid metabolism [5,6,8].

In HCC, METTL5 promotes glucose metabolic reprogramming, proliferation, and metastasis. Upregulation of METTL5 stabilizes c-Myc, activating downstream glycolytic genes. It does so by controlling USP5 translation, which in turn regulates c-Myc ubiquitination. Adenovirus-mediated knockout of METTL5 in patient-derived tumor xenograft (PDX) models shows good antitumor effects [1]. In intrahepatic cholangiocarcinoma (ICC), METTL5-mediated 18S rRNA m6A modification promotes cell growth and metastasis. METTL5 depletion impairs 18S rRNA m6A modification, hampers ribosome synthesis, and inhibits translation of G-quadruplex-containing mRNAs in the TGF-β pathway [2]. In gastric cancer, METTL5 promotes proliferation, migration, invasion, and cisplatin resistance, and its knockdown affects sphingomyelin metabolism [6]. In NSCLC, METTL5 interacts with IGF2BP3 to promote cancer cell proliferation [7]. In cranial suture development, Mettl5 knockout mice exhibit poor ossification, widened cranial sutures, and decreased osteogenic differentiation of suture mesenchymal stem cells due to down-regulation of Wnt signaling [5].

In conclusion, METTL5-mediated 18S rRNA m6A modification has far-reaching impacts on various biological functions and disease conditions. Gene knockout models, such as in HCC, ICC, gastric cancer, NSCLC, and craniofacial development studies, have been instrumental in revealing its oncogenic roles and potential as a therapeutic target in cancer, as well as its importance in craniofacial development. These findings contribute to a better understanding of the molecular mechanisms underlying disease processes and offer potential new strategies for treatment.

References:

1. Xia, Peng, Zhang, Hao, Lu, Haofeng, Zhang, Zhonglin, Yuan, Yufeng. 2023. METTL5 stabilizes c-Myc by facilitating USP5 translation to reprogram glucose metabolism and promote hepatocellular carcinoma progression. In Cancer communications (London, England), 43, 338-364. doi:10.1002/cac2.12403. https://pubmed.ncbi.nlm.nih.gov/36602428/

2. Dai, Zihao, Zhu, Wanjie, Hou, Yingdong, Lin, Shuibin, Kuang, Ming. 2023. METTL5-mediated 18S rRNA m6A modification promotes oncogenic mRNA translation and intrahepatic cholangiocarcinoma progression. In Molecular therapy : the journal of the American Society of Gene Therapy, 31, 3225-3242. doi:10.1016/j.ymthe.2023.09.014. https://pubmed.ncbi.nlm.nih.gov/37735874/

3. van Tran, Nhan, Ernst, Felix G M, Hawley, Ben R, Graille, Marc, Lafontaine, Denis L J. . The human 18S rRNA m6A methyltransferase METTL5 is stabilized by TRMT112. In Nucleic acids research, 47, 7719-7733. doi:10.1093/nar/gkz619. https://pubmed.ncbi.nlm.nih.gov/31328227/

4. Turkalj, Elena M, Vissers, Caroline. 2022. The emerging importance of METTL5-mediated ribosomal RNA methylation. In Experimental & molecular medicine, 54, 1617-1625. doi:10.1038/s12276-022-00869-y. https://pubmed.ncbi.nlm.nih.gov/36266443/

5. Lei, Kexin, Xu, Ruoshi, Wang, Qian, Zhou, Chenchen, Yuan, Quan. 2022. METTL5 regulates cranial suture fusion via Wnt signaling. In Fundamental research, 3, 369-376. doi:10.1016/j.fmre.2022.04.005. https://pubmed.ncbi.nlm.nih.gov/38933773/

6. Zhang, Ya-Qiong, Li, Jian, Qin, Zhe, Zhang, Xiao-Hong, Feng, Li. . METTL5 promotes gastric cancer progression via sphingomyelin metabolism. In World journal of gastrointestinal oncology, 16, 1925-1946. doi:10.4251/wjgo.v16.i5.1925. https://pubmed.ncbi.nlm.nih.gov/38764837/

7. Gong, Sihan, Liu, Hu, Gou, Hao, Sun, Wanli. 2024. METTL5: A Potential Biomarker for Nonsmall Cell Lung Cancer That Promotes Cancer Cell Proliferation by Interacting with IGF2BP3. In Genetic testing and molecular biomarkers, 28, 311-321. doi:10.1089/gtmb.2023.0531. https://pubmed.ncbi.nlm.nih.gov/39023781/

8. Peng, Hao, Chen, Binbin, Wei, Wei, Kuang, Ming, Lin, Shuibin. 2022. N6-methyladenosine (m6A) in 18S rRNA promotes fatty acid metabolism and oncogenic transformation. In Nature metabolism, 4, 1041-1054. doi:10.1038/s42255-022-00622-9. https://pubmed.ncbi.nlm.nih.gov/35999469/