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

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

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

13 Scopus citations


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.

Original languageEnglish (US)
Article number249
JournalGenome biology
Issue number1
StatePublished - Dec 2022


  • 6mA
  • Hypoxia
  • lncRNA
  • Metastasis
  • METTL4
  • ZMIZ1

ASJC Scopus subject areas

  • Ecology, Evolution, Behavior and Systematics
  • Genetics
  • Cell Biology


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