Journal Article

METTL4-mediated nuclear N6-deoxyadenosine methylation promotes metastasis through activating multiple metastasis-inducing targets

Pang, See-Tong, Chang, Chao-Hsiang, Chen, Ji-Lin, Chang, Jeng-Shou, Chang, Han, He, Chuan, Huang, Ching-Hui, Hsu, Kai-Wen, Wu, Kou-Juey, Lee, Der-Yen, Peng, Pei-Hua, Cui, Xiao-Long, Lai, Joseph Chieh-Yu, Tsai, Yu-Cheng, Chung, Chi-Jung, Hao, Ziyang

2022

Overview

Background DNA N6-methyldeoxyadenosine (6mA) is rarely present in mammalian cells and its nuclear role remains elusive. Results Here we show that hypoxia induces nuclear 6mA modification through a DNA methyltransferase, METTL4, in hypoxia-induced epithelial-mesenchymal transition (EMT) and tumor metastasis. Co-expression of METTL4 and 6mA represents a prognosis marker for upper tract urothelial cancer patients. By RNA sequencing and 6mA chromatin immunoprecipitation-exonuclease digestion followed by sequencing, we identify lncRNA RP11-390F4.3 and one novel HIF-1α co-activator, ZMIZ1, that are co-regulated by hypoxia and METTL4. Other genes involved in hypoxia-mediated phenotypes are also regulated by 6mA modification. Quantitative chromatin isolation by RNA purification assay shows the occupancy of lncRNA RP11-390F4.3 on the promoters of multiple EMT regulators, indicating lncRNA-chromatin interaction. Knockdown of lncRNA RP11-390F4.3 abolishes METTL4-mediated tumor metastasis. We demonstrate that ZMIZ1 is an essential co-activator of HIF-1α. Conclusions We show that hypoxia results in enriched 6mA levels in mammalian tumor cells through METTL4. This METTL4-mediated nuclear 6mA deposition induces tumor metastasis through activating multiple metastasis-inducing genes. METTL4 is characterized as a potential therapeutic target in hypoxic tumors.

• Publisher: BioMed Central,Springer Nature B.V,BMC
• Subject: 6mA / Animal Genetics and Genomics / Animals / Antibodies / Bioinformatics / Biomedical and Life Sciences / Bladder cancer / Cancer / Chromatin / Deoxyadenosine / Deoxyadenosines / digestion / DNA / DNA methylation / DNA methyltransferase / Epigenetics / Evolutionary Biology / Exonuclease / Experiments / Gene expression / genome / Human Genetics / Hypoxia / Hypoxia-inducible factor 1a / Immunoprecipitation / Life Sciences / lncRNA / Mammalian cells / Mammals / Mesenchyme / Metastases / Metastasis / Methylation / METTL4 / Microbial Genetics and Genomics / Mitochondria / Mitochondrial DNA / N6-methyladenosine / neoplasms / Non-coding RNA / Phenotypes / Plant Genetics and Genomics / prognosis / Reagents / RNA / RNA, Long Noncoding - genetics / Therapeutic targets / therapeutics / Tumor cells / Tumorigenesis / Tumors / Urinary Bladder Neoplasms / Urothelial cancer / ZMIZ1