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

被引:10
作者
Seehawer, Marco [1 ,2 ,3 ]
Li, Zheqi [1 ,2 ,3 ]
Nishida, Jun [1 ,2 ,3 ]
Foidart, Pierre [1 ,2 ,3 ]
Reiter, Andrew H. [4 ]
Rojas-Jimenez, Ernesto [1 ,2 ,3 ]
Goyette, Marie-Anne [1 ,2 ,3 ]
Yan, Pengze [1 ,2 ,3 ]
Raval, Shaunak [4 ]
Munoz Gomez, Miguel [5 ]
Cejas, Paloma [5 ]
Long, Henry W. [5 ]
Papanastasiou, Malvina [4 ]
Polyak, Kornelia [1 ,2 ,3 ]
机构
[1] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02118 USA
[2] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA
[3] Harvard Med Sch, Dept Med, Boston, MA 02115 USA
[4] Eli & Edythe L Broad Inst, Cambridge, MA USA
[5] Dana Farber Canc Inst, Ctr Funct Canc Epigenet, Boston, MA USA
基金
加拿大健康研究院;
关键词
SEQ DATA; CANCER; LANDSCAPE; RNA;
D O I
10.1038/s41556-024-01446-3
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
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.
引用
收藏
页码:1165 / 1175
页数:35
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