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Mitochondrial RNA methyltransferase TRMT61B is a new, potential biomarker and therapeutic target for highly aneuploid cancers

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Abstract

Despite being frequently observed in cancer cells, chromosomal instability (CIN) and its immediate consequence, aneuploidy, trigger adverse effects on cellular homeostasis that need to be overcome by anti-stress mechanisms. As such, these safeguard responses represent a tumor-specific Achilles heel, since CIN and aneuploidy are rarely observed in normal cells. Recent data have revealed that epitranscriptomic marks catalyzed by RNA-modifying enzymes change under various stress insults. However, whether aneuploidy is associated with such RNA modifying pathways remains to be determined. Through an in silico search for aneuploidy biomarkers in cancer cells, we found TRMT61B, a mitochondrial RNA methyltransferase enzyme, to be associated with high levels of aneuploidy. Accordingly, TRMT61B protein levels are increased in tumor cell lines with an imbalanced karyotype as well as in different tumor types when compared to control tissues. Interestingly, while TRMT61B depletion induces senescence in melanoma cell lines with low levels of aneuploidy, it leads to apoptosis in cells with high levels. The therapeutic potential of these results was further validated by targeting TRMT61B in transwell and xenografts assays. We show that TRM61B depletion reduces the expression of several mitochondrial encoded proteins and limits mitochondrial function. Taken together, these results identify a new biomarker of aneuploidy in cancer cells that could potentially be used to selectively target highly aneuploid tumors.

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Fig. 1: TRMT61B protein expression positively correlates with aneuploidy levels in human cell lines.
Fig. 2: TRMT61B expression is positively associated with cancer and aneuploidy levels in human cancers.
Fig. 3: TRMT61B overexpression fails to produce karyotype abnormalities, causes milder effects on cell biology, and does not promote tumor growth in vivo.
Fig. 4: Antiproliferative effects induced by TRMT61B knock-down in cell lines with different aneuploid levels.
Fig. 5: TRMT61B is required for mitochondrial functionality more prominently in ANEhigh cells.
Fig. 6: TRMT61B abrogation diminishes the tumorigenic potential of ANEhigh melanoma cell lines.

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The materials described in the manuscript, including all relevant raw data, will be freely available to any researcher wishing to use them for non-commercial purposes, without breaching participant confidentiality.

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Acknowledgements

We are deeply thankful to Oscar Fernández-Capetillo, María Salazar, and David Santamaría for their advice and scientific review of the manuscript. We acknowledge master thesis’ students Martín Salamini and Sarai Araujo for their support in the performance of several in vitro experiments. We thank the research groups led by Zuzana Strochova, Iain Chesseman, Bon-Kyoung Koo, Amparo Cano, Marisol Soengas, and Marcos Malumbres for providing us with cell lines and reagents used in this study. We would also like to thank Daniel Luque and María del Carmen Terrón, members of the Electron Microscopy Unit from ISCIII, for their technical assistance. All the illustrations included in the figures were created with the help of biorender.com.

Funding

AM was a recipient of a postdoctoral fellowship from the Fundación Española Contra el Cáncer (AECC). This study was supported by grants from the Spanish Ministry of Science and Innovation (to IPC, SAF2016-76929-R) and from the Acción Estratégica de Salud Intramural (to A.M., PI17CIII/00010).

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AM acquired, analyzed, and interpreted most of the data; BV-M, IH, DG-D, and SA assist with several in vitro experiments; BV-M, IH and CE helped with mouse xenograft experiments; BV-M prepared cell cultures for karyotype analyses; CE performed mitochondrial ultrastructural analysis; AC, MGC, ARM, and SV carried out the Seahorse studies; RIRM provided liver samples and performed the subsequent histological analysis; EC is our in-house pathologist and assisted with histological analysis of TMAs and xenograft tumors; RB and MGA performed ELISA assays and collected plasma from normal and colon patients; JC provided additional plasma samples from breast, ovary and lung tumor bearing patients; AM-R performed karyotype analysis; PC-S and LS designed and performed the zebrafish studies. GG-L carried out bioinformatics and clustering analyses. IPC and AM developed the study concept, obtained funding, interpreted the data, and drafted/edited the manuscript; and all the authors edited the manuscript.

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Correspondence to Alberto Martín or Ignacio Pérez de Castro.

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All the experiments of the study were carried out in accordance with the Declaration of Helsinki. All mouse studies were performed in compliance with the institutional guidelines for the welfare of experimental animals approved by the Use Committee for Animal Care from Instituto de Salud Carlos III (ISCIII) and La Comunidad de Madrid and in accordance with the guidelines for Ethical Conduct in the Care and Use of Animals as stated in The International Guiding Principles for Biomedical Research involving Animals, developed by the Council for International Organizations of Medical Sciences (CIOMS). All the procedures used in the zebrafish experiments as well as fish care were performed in agreement with the Animal Care and Use Committee of the University of Santiago de Compostela and the standard protocols of Spain (Directive 2012-63-UE). At the final point of the experiments, zebrafish embryos were euthanized by tricaine overdose. Liver samples were obtained from patients having undergone surgical resection at the University Hospital of Salamanca, Spain. The study was approved by the Ethics Committee for Clinical Research of Salamanca (July 18, 2018) and informed written consent for the samples to be used for biomedical research was obtained from each patient. Plasma samples were obtained from the biobank of the Hospital Clínico San Carlos or provided by Hospital Universitari de Sant Joan (Tarragona, Spain) after approval of the Ethical Review Boards of these institutions. All subjects in the study gave their written informed consent to participate and all experiments were performed in accordance with relevant guidelines and regulations.

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Martín, A., Epifano, C., Vilaplana-Marti, B. et al. Mitochondrial RNA methyltransferase TRMT61B is a new, potential biomarker and therapeutic target for highly aneuploid cancers. Cell Death Differ (2022). https://doi.org/10.1038/s41418-022-01044-6

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