METTL14, also known as methyltransferase-like 14, is a major RNA N6-adenosine methyltransferase. It is involved in the m6A modification of RNA, which is an important epigenetic regulation affecting RNA function, including stability, translation, and splicing. This modification participates in numerous biological processes such as cell differentiation, development, and metabolism [1-10].

In colorectal cancer, METTL14 expression is downregulated, and its decrease is associated with poor overall survival. METTL14 inhibits CRC cells' migration, invasion, and metastasis both in vitro and in vivo by mediating m6A modification of SOX4 mRNA [1]. In p53-wild-type CRC cells, METTL14 is transcriptionally activated by wild-type p53, suppressing tumor growth and restraining aerobic glycolysis [2].

In diabetic cardiomyopathy, METTL14 is downregulated in cardiomyocytes and heart tissues of DCM rats. It suppresses pyroptosis and DCM via downregulating lncRNA TINCR [3].

In endothelial inflammation and atherosclerosis, METTL14 promotes FOXO1 expression by enhancing its m6A modification, leading to endothelial cell inflammatory response and atherosclerotic plaque formation [4].

In normal and malignant hematopoiesis, METTL14 inhibits hematopoietic stem/progenitor differentiation and promotes leukemogenesis via mRNA m6A modification [5].

In chemotherapy-induced neuropathic pain, METTL14-mediated m6A modification in DRG neurons maintains neuropathic pain by stabilizing GluN2A expression [6].

After ischemic stroke, METTL14 promotes M1 polarization and NLRP3 inflammasome/pyroptosis axis in microglia/macrophage [7].

In the heart, METTL14 is required for exercise-induced cardiac hypertrophy and protects against myocardial ischemia-reperfusion injury [8].

In CRC, METTL14 also suppresses proliferation and metastasis by down-regulating oncogenic lncRNA XIST [9].

In conclusion, METTL14 plays a crucial role in multiple biological processes and disease conditions through its m6A-modifying function. Gene knockout and conditional knockout mouse models have been instrumental in revealing its role in diseases like colorectal cancer, diabetic cardiomyopathy, atherosclerosis, and others. Understanding METTL14 provides insights into the epigenetic regulation underlying these diseases, potentially leading to new therapeutic strategies.

References:

1. Chen, Xiaoxiang, Xu, Mu, Xu, Xueni, Sun, Huilin, Wang, Shukui. 2020. METTL14-mediated N6-methyladenosine modification of SOX4 mRNA inhibits tumor metastasis in colorectal cancer. In Molecular cancer, 19, 106. doi:10.1186/s12943-020-01220-7. https://pubmed.ncbi.nlm.nih.gov/32552762/

2. Hou, Yichao, Zhang, Xintian, Yao, Han, Fang, Jing-Yuan, Meng, Xiangjun. 2023. METTL14 modulates glycolysis to inhibit colorectal tumorigenesis in p53-wild-type cells. In EMBO reports, 24, e56325. doi:10.15252/embr.202256325. https://pubmed.ncbi.nlm.nih.gov/36794620/

3. Meng, Liping, Lin, Hui, Huang, Xingxiao, Peng, Fang, Wu, Shengjie. 2022. METTL14 suppresses pyroptosis and diabetic cardiomyopathy by downregulating TINCR lncRNA. In Cell death & disease, 13, 38. doi:10.1038/s41419-021-04484-z. https://pubmed.ncbi.nlm.nih.gov/35013106/

4. Jian, Dongdong, Wang, Ying, Jian, Liguo, Wang, Shuai, Li, Muwei. 2020. METTL14 aggravates endothelial inflammation and atherosclerosis by increasing FOXO1 N6-methyladeosine modifications. In Theranostics, 10, 8939-8956. doi:10.7150/thno.45178. https://pubmed.ncbi.nlm.nih.gov/32802173/

5. Weng, Hengyou, Huang, Huilin, Wu, Huizhe, He, Chuan, Chen, Jianjun. 2017. METTL14 Inhibits Hematopoietic Stem/Progenitor Differentiation and Promotes Leukemogenesis via mRNA m6A Modification. In Cell stem cell, 22, 191-205.e9. doi:10.1016/j.stem.2017.11.016. https://pubmed.ncbi.nlm.nih.gov/29290617/

6. Lu, Weicheng, Yang, Xiaohua, Zhong, Weiqiang, Ma, Huijie, Xie, Jingdun. 2024. METTL14-mediated m6A epitranscriptomic modification contributes to chemotherapy-induced neuropathic pain by stabilizing GluN2A expression via IGF2BP2. In The Journal of clinical investigation, 134, . doi:10.1172/JCI174847. https://pubmed.ncbi.nlm.nih.gov/38319733/

7. Li, Yamei, Li, Jiacen, Yu, Qian, Ji, Ling, Peng, Bo. 2023. METTL14 regulates microglia/macrophage polarization and NLRP3 inflammasome activation after ischemic stroke by the KAT3B-STING axis. In Neurobiology of disease, 185, 106253. doi:10.1016/j.nbd.2023.106253. https://pubmed.ncbi.nlm.nih.gov/37541353/

8. Wang, Lijun, Wang, Jiaqi, Yu, Pujiao, Sluijter, Joost P G, Xiao, Junjie. 2022. METTL14 is required for exercise-induced cardiac hypertrophy and protects against myocardial ischemia-reperfusion injury. In Nature communications, 13, 6762. doi:10.1038/s41467-022-34434-y. https://pubmed.ncbi.nlm.nih.gov/36351918/

9. Yang, Xiao, Zhang, Sen, He, Changyu, Sun, Jing, Zheng, Minhua. 2020. METTL14 suppresses proliferation and metastasis of colorectal cancer by down-regulating oncogenic long non-coding RNA XIST. In Molecular cancer, 19, 46. doi:10.1186/s12943-020-1146-4. https://pubmed.ncbi.nlm.nih.gov/32111213/