Heterozygous Kmt2d loss diminishes enhancers to render medulloblastoma cells vulnerable to combinatory inhibition of lysine demethylation and oxidative phosphorylation.
Heterozygous Kmt2d loss diminishes enhancers to render medulloblastoma cells vulnerable to combinatory inhibition of lysine demethylation and oxidative phosphorylation.
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杂合 Kmt2d 缺失会减少增强子，使髓母细胞瘤细胞容易受到赖氨酸去甲基化和氧化磷酸化的联合抑制。
DOI：
10.1101/2023.10.29.564587
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发表时间：
2023
期刊：
影响因子：
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通讯作者：
Lee,MinGyu
中科院分区：
文献类型：
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作者：
Dhar,ShilpaS;Brown,Calena;Rizvi,Ali;Reed,Lauren;Kotla,Sivareddy;Zod,Constantin;Abraham,Janak;Abe,Jun-Ichi;Rajaram,Veena;Chen,Kaifu;Lee,MinGyu
组蛋白 H3 赖氨酸 4 (H3K4) 甲基转移酶 KMT2D（也称为 MLL4）是许多癌症（包括髓母细胞瘤 (MB)）中最常见突变的表观遗传修饰因子之一。值得注意的是，杂合 KMT2D 缺失经常发生在 MB 和其他癌症中。然而，其致癌作用在很大程度上仍不为人所知。在这里，我们表明，小鼠小脑区域的杂合 Kmt2dloss 通过上调肿瘤促进程序（例如氧化磷酸化 [OXPHOS]），促进 MB 生成，这是由 MB 抑制基因 Ptch 的杂合缺失驱动的。杂合子 Kmt2dloss 下调转录抑制性肿瘤抑制因子 NCOR2，以及 Ptch+/- 增加 MYCN，上调肿瘤促进基因。杂合Kmt2dloss 显着减少了增强子标记（H3K4me1 和 H3K27ac）和 H3K4me3 签名，包括 Ncor2 的标记。增强子停用 H3K4 去甲基酶 LSD1 和 OXPHOS 的联合药理学抑制显着降低了携带杂合 Kmt2dloss 的 MB 细胞的致瘤性。我们的研究结果表明杂合 KMT2Dloss 的 MB 促进作用背后的分子和表观遗传发病机制。
The histone H3 lysine 4 (H3K4) methyltransferase KMT2D (also called MLL4) is one of the most frequently mutated epigenetic modifiers in many cancers, including medulloblastoma (MB). Notably, heterozygousKMT2Dloss frequently occurs in MB and other cancers. However, its oncogenic role remains largely uncharacterized. Here, we show that heterozygousKmt2dloss in murine cerebellar regions promotes MB genesis driven by heterozygous loss of the MB-suppressor genePtchvia the upregulation of tumor-promoting programs (e.g., oxidative phosphorylation [OXPHOS]). Downregulation of the transcription-repressive tumor suppressor NCOR2 by heterozygousKmt2dloss, along withPtch+/−-increased MYCN, upregulated tumor-promoting genes. HeterozygousKmt2dloss substantially diminished enhancer marks (H3K4me1 and H3K27ac) and the H3K4me3 signature, including those forNcor2. Combinatory pharmacological inhibition of the enhancer-decommissioning H3K4 demethylase LSD1 and OXPHOS significantly reduced the tumorigenicity of MB cells bearing heterozygousKmt2dloss. Our findings suggest the molecular and epigenetic pathogenesis underlying the MB-promoting effect of heterozygousKMT2Dloss.