美国丹娜-法伯癌症研究所Kornelia Polyak团队近期取得重要工作进展，他们研究提出，Kmt2c或Kmt2d的缺失通过KDM6A依赖性MMP3的上调驱动脑转移。相关研究成果2024年6月26日在线发表于《自然—细胞生物学》杂志上。

据介绍，KMT2C和KMT2D编码组蛋白H3赖氨酸4甲基转移酶，是三阴性乳腺癌（TNBC）中最常见的突变基因。然而，这些突变如何形成表观基因组和转录组表型以促进肿瘤发生在很大程度上是未知的。

研究人员描述了TNBC的非转移性小鼠模型中Kmt2c或Kmt2d的缺失驱动转移，特别是向大脑的转移。测序后的整体染色质分析和染色质免疫沉淀显示，在Kmt2c或Kmt2d敲除细胞中，H3K4me1、H3K27ac和H3K27me3染色质标记发生改变，H3K27me3赖氨酸去甲基酶KDM6A的结合增强，这与基因表达显著相关。

研究人员发现，在两种敲除模型中，Mmp3在通过表观遗传学机制普遍上调。与这些发现一致，来自KMT2C突变TNBC患者的样本具有较高的MMP3水平。KDM6A的下调或药理学抑制减少了组蛋白-赖氨酸N-甲基转移酶2（KMT2）缺失诱导的Mmp3上调，并阻止了脑转移，类似于Mmp3的直接下调。

总之，研究人员确定KDM6A-基质金属蛋白酶3轴是TNBC中KMT2C/D损失驱动转移的关键介质。

附：英文原文

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

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

Issue&Volume: 2024-06-26

Abstract: 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.

DOI: 10.1038/s41556-024-01446-3

Source: https://www.nature.com/articles/s41556-024-01446-3