Reinvestigating the clinical relevance of the m6A writer METTL3 in urothelial carcinoma of the bladder

Jonas Koch; Manuel Neuberger; Martina Schmidt-Dengler; Jinyun Xu; Vitor Coutinho Carneiro; Jörg Ellinger; Maximilian C Kriegmair; Philipp Nuhn; Philipp Erben; Maurice Stephan Michel; Mark Helm; Manuel Rodríguez-Paredes; Malin Nientiedt; Frank Lyko

doi:10.1016/j.isci.2023.107300

Reinvestigating the clinical relevance of the m⁶A writer METTL3 in urothelial carcinoma of the bladder

iScience. 2023 Jul 11;26(8):107300. doi: 10.1016/j.isci.2023.107300. eCollection 2023 Aug 18.

Affiliations

¹ Division of Epigenetics, DKFZ-ZMBH Alliance, German Cancer Research Center, 69120 Heidelberg, Germany.
² Department of Urology and Urosurgery, Medical Faculty Mannheim, University of Heidelberg, 68167 Mannheim, Germany.
³ Institute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg-Universität, 55128 Mainz, Germany.
⁴ Department of Urology, University Hospital Bonn, 53127 Bonn, Germany.

Abstract

METTL3 is the major writer of N6-Methyladenosine (m⁶A) and has been associated with controversial roles in cancer. This is best illustrated in urothelial carcinoma of the bladder (UCB), where METTL3 was described to have both oncogenic and tumor-suppressive functions. Here, we reinvestigated the role of METTL3 in UCB. METTL3 knockout reduced the oncogenic phenotype and m⁶A levels of UCB cell lines. However, complete depletion of METTL3/m⁶A was not achieved due to selection of cells expressing alternative METTL3 isoforms. Systematic vulnerability and inhibitor response analyses suggested that uroepithelial cells depend on METTL3 for viability. Furthermore, expression and survival analyses of clinical data revealed a complex role for METTL3 in UCB, with decreased m⁶A mRNA levels in UCB tumors. Our results suggest that METTL3 expression may be a suitable diagnostic UCB biomarker, as the enzyme promotes UCB formation. However, the suitability of the enzyme as a therapeutic target should be evaluated carefully.

Keywords: Biological sciences; Cancer systems biology; Epigenetics; Molecular biology; Molecular mechanism of gene regulation; Natural sciences; Oncology; Systems biology.