METTL3, short for methyltransferase-like 3, is the sole catalytic subunit of the methyltransferase complex that catalyzes N6-methyladenosine (m6A) modification, the most abundant mRNA modification. m6A modification is involved in numerous biological processes such as gene expression regulation, RNA splicing, and translation [2].

In cancer research, myeloid deficiency of METTL3 attenuated tumor growth in mice, suggesting its role in promoting tumor immune escape in colon cancer as it mediates m6A modification on Jak1 mRNA in tumor-infiltrating myeloid cells (TIMs), enhancing JAK1 protein translation and STAT3 phosphorylation [1]. In small cell lung cancer, METTL3 is highly expressed in chemoresistant cells and promotes chemoresistance by positively regulating mitophagy through m6A methylation of DCP2, and its inhibitor STM2457 can reverse chemoresistance [3]. In breast cancer, METTL3 knockdown reduces PD-L1 mRNA stabilization, and inhibition of METTL3 enhances anti-tumor immunity [4]. In papillary thyroid cancer, downregulation of METTL3 is correlated with poor prognosis, and it plays a tumor-suppressor role through c-Rel and RelA inactivation of the NF-κB pathway and altered neutrophil infiltration [5]. In intrahepatic cholangiocarcinoma, METTL3 promotes cancer progression by regulating IFIT2 expression in an m6A-YTHDF2-dependent manner, and its inhibitor also shows anti-tumor effects [7]. In colorectal cancer, METTL3 promotes cancer cell proliferation and metastasis by activating the JAK1/STAT3 signaling pathway in both methyltransferase activity-dependent and-independent ways [6].

In summary, METTL3 is crucial in regulating m6A modification and has significant impacts on various biological processes, especially in cancer development and progression. The use of KO/CKO mouse models in these studies has revealed the multifaceted roles of METTL3 in different cancer types, providing potential therapeutic targets for cancer treatment.

References:

1. Xiong, Jia, He, Jia, Zhu, Jun, Lai, Lihua, Wang, Qingqing. 2022. Lactylation-driven METTL3-mediated RNA m6A modification promotes immunosuppression of tumor-infiltrating myeloid cells. In Molecular cell, 82, 1660-1677.e10. doi:10.1016/j.molcel.2022.02.033. https://pubmed.ncbi.nlm.nih.gov/35320754/

2. Zeng, Chengwu, Huang, Wanxu, Li, Yangqiu, Weng, Hengyou. 2020. Roles of METTL3 in cancer: mechanisms and therapeutic targeting. In Journal of hematology & oncology, 13, 117. doi:10.1186/s13045-020-00951-w. https://pubmed.ncbi.nlm.nih.gov/32854717/

3. Sun, Yueqin, Shen, Weitao, Hu, Shulu, Zhu, Weiliang, Zhang, Jian. 2023. METTL3 promotes chemoresistance in small cell lung cancer by inducing mitophagy. In Journal of experimental & clinical cancer research : CR, 42, 65. doi:10.1186/s13046-023-02638-9. https://pubmed.ncbi.nlm.nih.gov/36932427/

4. Wan, Weijun, Ao, Xiang, Chen, Quan, Luo, Donglin, Xu, Xiang. 2022. METTL3/IGF2BP3 axis inhibits tumor immune surveillance by upregulating N6-methyladenosine modification of PD-L1 mRNA in breast cancer. In Molecular cancer, 21, 60. doi:10.1186/s12943-021-01447-y. https://pubmed.ncbi.nlm.nih.gov/35197058/

5. He, Jing, Zhou, Mingxia, Yin, Jie, Yin, Huiqing, He, Fucheng. 2021. METTL3 restrains papillary thyroid cancer progression via m6A/c-Rel/IL-8-mediated neutrophil infiltration. In Molecular therapy : the journal of the American Society of Gene Therapy, 29, 1821-1837. doi:10.1016/j.ymthe.2021.01.019. https://pubmed.ncbi.nlm.nih.gov/33484966/

6. Sun, Yuechao, Gong, Weipeng, Zhang, Song. 2023. METTL3 promotes colorectal cancer progression through activating JAK1/STAT3 signaling pathway. In Cell death & disease, 14, 765. doi:10.1038/s41419-023-06287-w. https://pubmed.ncbi.nlm.nih.gov/38001065/

7. Xu, Qiong-Cong, Tien, Yi-Chih, Shi, Yin-Hao, Zhao, Wei, Yin, Xiao-Yu. 2022. METTL3 promotes intrahepatic cholangiocarcinoma progression by regulating IFIT2 expression in an m6A-YTHDF2-dependent manner. In Oncogene, 41, 1622-1633. doi:10.1038/s41388-022-02185-1. https://pubmed.ncbi.nlm.nih.gov/35094011/