EBF2 Links KMT2D-Mediated H3K4me1 to Suppress Pancreatic Cancer Progression via Upregulating KLLN.
EBF2 Links KMT2D-Mediated H3K4me1 to Suppress Pancreatic Cancer Progression via Upregulating KLLN.
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DOI：
10.1002/advs.202302037
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发表时间：
2024-01
期刊：
影响因子：
15.1
通讯作者：
Ma, Changyan
中科院分区：
文献类型：
--
作者：
Yao, Bing;Xing, Mengying;Meng, Shixin;Li, Shang;Zhou, Jingwan;Zhang, Ming;Yang, Chen;Qu, Shuang;Jin, Yucui;Yuan, Hongyan;Zen, Ke;Ma, Changyan
由组蛋白赖氨酸N-甲基转移酶2D（KMT 2D）催化的组蛋白H3在赖氨酸4上的单甲基化（H3 K4 me 1）在转录控制中充当重要的表观遗传调节剂。在这项研究中，作者鉴定了早期B-细胞因子2（EBF 2）作为H3 K4 me 1的结合蛋白。结合RNA-seq和ChIP-seq数据的分析，作者进一步鉴定了KLLN作为胰腺导管腺癌（PDAC）细胞中KMT 2D和EBF 2的转录靶点。KMT 2D依赖性H3 K4 me 1和EBF 2主要在KLLN基因的转录起始位点（TSS）附近重叠。综合功能分析显示，KMT 2D和EBF 2通过上调KLLN协同抑制PDAC细胞增殖、迁移和侵袭。这种对PDAC进展的抑制也通过GSK-LSD 1（赖氨酸特异性脱甲基酶1（LSD 1）的选择性抑制剂）增加H3 K4 me 1水平来实现。总之，这些发现揭示了PDAC进展的新机制，并为PDAC治疗提供了潜在的治疗靶点。EBF 2是一种新的H3 K4 me 1结合蛋白。EBF 2和KMT 2D协同调节H3 K4 me 1，导致KLLN表达的表观遗传激活和PDAC进展的强烈抑制。这种对PDAC进展的抑制也通过LSD 1的选择性抑制剂GSK-LSD 1增加H3 K4 me 1水平来实现。这些发现揭示了PDAC进展的新病理机制，并为PDAC治疗提供了潜在的治疗靶点。
Mono‐methylation of histone H3 on Lys 4 (H3K4me1), which is catalyzed by histone‐lysine N‐methyltransferase 2D (KMT2D), serves as an important epigenetic regulator in transcriptional control. In this study, the authors identify early B‐cell factor 2 (EBF2) as a binding protein of H3K4me1. Combining analyses of RNA‐seq and ChIP‐seq data, the authors further identify killin (KLLN) as a transcriptional target of KMT2D and EBF2 in pancreatic ductal adenocarcinoma (PDAC) cells. KMT2D‐dependent H3K4me1 and EBF2 are predominantly over‐lapped proximal to the transcription start site (TSS) of KLLN gene. Comprehensive functional assays show that KMT2D and EBF2 cooperatively inhibit PDAC cells proliferation, migration, and invasion through upregulating KLLN. Such inhibition on PDAC progression is also achieved through increasing H3K4me1 level by GSK‐LSD1, a selective inhibitor of lysine‐specific demethylase 1 (LSD1). Taken together, these findings reveal a new mechanism underlying PDAC progression and provide potential therapeutic targets for PDAC treatment. EBF2 is a novel H3K4me1‐binding protein. EBF2 and KMT2D cooperatively regulate H3K4me1, leading to epigenetically activation of KLLN expression and strongly inhibition of PDAC progression. Such inhibition on PDAC progression is also achieved through increasing H3K4me1 level by GSK‐LSD1, a selective inhibitor of LSD1. These findings reveal a novel pathologic mechanism underlying PDAC progression and provide potential therapeutic targets for PDAC treatment.
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影响因子：
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作者：
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通讯作者：
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影响因子：
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作者：
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