Journal Article

Loss of Kmt2c or Kmt2d drives brain metastasis via KDM6A-dependent upregulation of MMP3

Li, Zheqi, Raval, Shaunak, Long, Henry W., Reiter, Andrew H., Foidart, Pierre, Rojas-Jimenez, Ernesto, Yan, Pengze, Papanastasiou, Malvina, Munoz Gomez, Miguel, Polyak, Kornelia, Seehawer, Marco, Cejas, Paloma, Goyette, Marie-Anne, Nishida, Jun

2024

Overview

KMT2C and KMT2D , encoding histone H3 lysine 4 methyltransferases, are among the most commonly mutated genes in triple-negative breast cancer (TNBC). However, how these mutations may shape epigenomic and transcriptomic landscapes to promote tumorigenesis is largely unknown. Here we describe that deletion of Kmt2c or Kmt2d in non-metastatic murine models of TNBC drives metastasis, especially to the brain. Global chromatin profiling and chromatin immunoprecipitation followed by sequencing revealed altered H3K4me1, H3K27ac and H3K27me3 chromatin marks in knockout cells and demonstrated enhanced binding of the H3K27me3 lysine demethylase KDM6A, which significantly correlated with gene expression. We identified Mmp3 as being commonly upregulated via epigenetic mechanisms in both knockout models. Consistent with these findings, samples from patients with KMT2C- mutant TNBC have higher MMP3 levels. Downregulation or pharmacological inhibition of KDM6A diminished Mmp3 upregulation induced by the loss of histone–lysine N -methyltransferase 2 (KMT2) and prevented brain metastasis similar to direct downregulation of Mmp3 . Taken together, we identified the KDM6A–matrix metalloproteinase 3 axis as a key mediator of KMT2C/D loss-driven metastasis in TNBC. Seehawer et al. show that deletion of Kmt2c or Kmt2d promotes brain metastasis in mouse models of triple-negative breast cancer due to altered KDM6A activity and upregulated MMP3 expression, which may constitute a potential therapeutic target.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Research
• Subject: 38/23 / 38/35 / 38/39 / 38/77 / 38/79 / 38/91 / 631/208/68 / 631/67/1347 / 631/67/322 / Animal models / Animals / Biomedical and Life Sciences / Brain / Brain cancer / Brain Neoplasms / Brain Neoplasms - genetics / Brain Neoplasms - metabolism / Brain Neoplasms - pathology / Brain Neoplasms - secondary / Breast cancer / Cancer Research / Cell Biology / Cell Line, Tumor / Chromatin / Deletion / Developmental Biology / DNA-Binding Proteins / DNA-Binding Proteins - genetics / DNA-Binding Proteins - metabolism / Down-regulation / Epigenesis, Genetic / Epigenetics / Female / Gene deletion / Gene expression / Gene Expression Regulation, Neoplastic / Histone Demethylases / Histone Demethylases - genetics / Histone Demethylases - metabolism / Histone H3 / Histone methyltransferase / Histone-Lysine N-Methyltransferase / Histone-Lysine N-Methyltransferase - genetics / Histone-Lysine N-Methyltransferase - metabolism / Histones / Human health sciences / Humans / Immunoprecipitation / KDM6A protein, human / KMT2C protein, human / KMT2D protein, human / Kmt2d protein, mouse / Life Sciences / Lysine / Matrix metalloproteinase / Matrix Metalloproteinase 3 / Matrix Metalloproteinase 3 - genetics / Matrix Metalloproteinase 3 - metabolism / Matrix metalloproteinases / Metalloproteinase / Metastases / Metastasis / Mice / Mice, Knockout / MMP3 protein, human / Myeloid-Lymphoid Leukemia Protein / N-Methyltransferase / Neoplasm Proteins / Neoplasm Proteins - genetics / Neoplasm Proteins - metabolism / Oncologie / Oncology / Sciences de la santé humaine / Stem Cells / Stromelysin 1 / Therapeutic targets / Transcriptomics / Triple Negative Breast Neoplasms / Triple Negative Breast Neoplasms - genetics / Triple Negative Breast Neoplasms - metabolism / Triple Negative Breast Neoplasms - pathology / Tumorigenesis / Up-Regulation