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. 2022 Dec 2;23:249. doi: 10.1186/s13059-022-02819-3

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© The Author(s) 2022

Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

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Fig. 3 — The essential role of the enzymatic activity of METTL4 in hypoxia-induced phenotypes and clinical implications. a Mutation of the enzymatic site of METTL4 by a prime-cutting CRISPR-Cas9 approach in BFTC909 cells abolished the induction of EMT by hypoxia and significantly decreased the RNA expression of RP11-390F4.3 and Glut1. The induction of 6mA levels was abolished in enzymatically inactive METTL4 mutant BFTC909 cells. N, normoxia; H, hypoxia. The normoxic condition for METTL4 wild type BFTC909 cells was used as a control. A corresponding 6mA dot blot with methyl blue loading control is shown together with the bar graph. The asterisk (*) indicated statistical significance (P<0.05) between experimental and control groups. b Immunofluorescence staining shows the abolishment of EMT induction by hypoxia in the enzymatically inactive METTL4 mutant FADU and BFTC909 cells. Green fluorescence represented staining of E-cadherin; red fluorescence represented staining of vimentin. Cell nuclei were stained by DAPI. N, normoxia; H, hypoxia. The normoxic condition for METTL4 wild type BFTC909 and FADU cells were used as a control. c Increased 6mA levels in UTUC, but not in bladder cancer (BC), patient samples. d Increased METTL4, 6mA, and HIF-1α levels by immunohistochemistry staining in the tumor part (T) (vs. the normal part (N)) of UTUC patient samples are shown by H-score measurement. The error bars represented the standard deviation (SD). Student’s t test was used to compare two groups of independent samples. e A representative case of immunohistochemistry staining of UTUC patient samples using antibodies against METTL4, 6mA, and HIF-1α between normal and tumor tissues. f Co-expression of METTL4 and 6mA predicted a poor prognosis of UTUC patients in either overall survival or disease-free survival by Kaplan-Meier analysis. Subgroup analysis of overall survival and disease-free survival of UTUC cases according to the expression profile of METTL4 low/6mA low (Group 1), METTL4 high/6mA high (Group 2), and others (Group 3) in tumors. P values of the comparison between each group are shown