2. Academic Validation
  3. Loss of Kmt2c in vivo leads to EMT, mitochondrial dysfunction and improved response to lapatinib in breast cancer

Loss of Kmt2c in vivo leads to EMT, mitochondrial dysfunction and improved response to lapatinib in breast cancer

  • Cell Mol Life Sci. 2023 Mar 18;80(4):100. doi: 10.1007/s00018-023-04734-7.
Nikiana Simigdala 1,  Anna Chalari 2,  Aimilia D Sklirou 3,  Evangelia Chavdoula 2 4 5,  George Papafotiou 2,  Pelagia Melissa 2,  Aimilia Kafalidou 2,  Nikolaos Paschalidis 2,  Ioannis S Pateras 6,  Emmanouil Athanasiadis 2,  Dimitris Konstantopoulos 7,  Ioannis P Trougakos 3,  Apostolos Klinakis 8
Affiliations

Affiliations

  • 1 Biomedical Research Foundation Academy of Athens, Athens, Greece. nsimigdala@bioacademy.gr.
  • 2 Biomedical Research Foundation Academy of Athens, Athens, Greece.
  • 3 Department of Cell Biology and Biophysics, Faculty of Biology, National and Kapodistrian University of Athens, Athens, Greece.
  • 4 Department of Cancer Biology and Genetics, The Ohio State University, Columbus, OH, USA.
  • 5 The Ohio State University Comprehensive Cancer Center-Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, Columbus, OH, USA.
  • 6 2nd Department of Pathology, Medical School, "Attikon" University Hospital, National and Kapodistrian University of Athens, Athens, Greece.
  • 7 Institute for Fundamental Biomedical Research, BSRC 'Alexander Fleming', 16672, Vari, Greece.
  • 8 Biomedical Research Foundation Academy of Athens, Athens, Greece. aklinakis@bioacademy.gr.
PMID: 36933062 DOI: 10.1007/s00018-023-04734-7
Abstract

Deep Sequencing of human tumours has uncovered a previously unappreciated role for epigenetic regulators in tumorigenesis. H3K4 methyltransferase KMT2C/MLL3 is mutated in several solid malignancies, including more than 10% of breast tumours. To study the tumour suppressor role of KMT2C in breast Cancer, we generated mouse models of Erbb2/Neu, Myc or PIK3CA-driven tumorigenesis, in which the Kmt2c locus is knocked out specifically in the luminal lineage of mouse mammary glands using the Cre recombinase. Kmt2c knock out mice develop tumours earlier, irrespective of the oncogene, assigning a bona fide tumour suppressor role for KMT2C in mammary tumorigenesis. Loss of Kmt2c induces extensive epigenetic and transcriptional changes, which lead to increased ERK1/2 activity, extracellular matrix re-organization, epithelial-to-mesenchymal transition and mitochondrial dysfunction, the latter associated with increased Reactive Oxygen Species production. Loss of Kmt2c renders the Erbb2/Neu-driven tumours more responsive to lapatinib. Publicly available clinical datasets revealed an association of low Kmt2c gene expression and better long-term outcome. Collectively, our findings solidify the role of KMT2C as a tumour suppressor in breast Cancer and identify dependencies that could be therapeutically amenable.

Keywords

Breast cancer; EMT; KMT2C; Lapatinib; Mitochondrial respiration; Tumour suppressor.

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