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

Menée à l'aide de lignées cellulaires et de modèles murins de tumeur mammaire triple négative non métastatique, cette étude met en évidence un mécanisme par lequel la délétion des gènes KMT2C et KMT2D, impliqués dans le codage des méthyltransférases ciblant la lysine 4 des histones 3, favorise le développement de métastases cérébrales via la déméthylase KDM6A et la métalloprotéase MMP3

Résumé en anglais

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.