Department of Surgery, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA.
Center for Applied Bioinformatics, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA.
Nat Commun. 2021 Dec 10;12(1):7204. doi: 10.1038/s41467-021-27502-2.
The H3K27me2/me3 histone demethylase KDM6B is essential to neuroblastoma cell survival. However, the mechanism of KDM6B action remains poorly defined. We demonstrate that inhibition of KDM6B activity 1) reduces the chromatin accessibility of E2F target genes and MYCN, 2) selectively leads to an increase of H3K27me3 but a decrease of the enhancer mark H3K4me1 at the CTCF and BORIS binding sites, which may, consequently, disrupt the long-range chromatin interaction of MYCN and E2F target genes, and 3) phenocopies the transcriptome induced by the specific CDK4/6 inhibitor palbociclib. Overexpression of CDK4/6 or Rb1 knockout confers neuroblastoma cell resistance to both palbociclib and the KDM6 inhibitor GSK-J4. These data indicate that KDM6B promotes an oncogenic CDK4/6-pRB-E2F pathway in neuroblastoma cells via H3K27me3-dependent enhancer-promoter interactions, providing a rationale to target KDM6B for high-risk neuroblastoma.
H3K27me2/me3 组蛋白去甲基化酶 KDM6B 对神经母细胞瘤细胞的存活至关重要。然而，KDM6B 的作用机制仍未明确定义。我们证明，抑制 KDM6B 的活性：1）降低 E2F 靶基因和 MYCN 的染色质可及性；2）选择性地导致 H3K27me3 的增加，而 CTCF 和 BORIS 结合位点的增强子标记 H3K4me1 的减少，这可能随后破坏 MYCN 和 E2F 靶基因的长程染色质相互作用；3）模拟由特异性 CDK4/6 抑制剂 palbociclib 诱导的转录组。CDK4/6 过表达或 Rb1 敲除使神经母细胞瘤细胞对 palbociclib 和 KDM6 抑制剂 GSK-J4 均产生耐药性。这些数据表明，KDM6B 通过 H3K27me3 依赖性增强子-启动子相互作用促进神经母细胞瘤细胞中的致癌 CDK4/6-pRB-E2F 通路，为针对高危神经母细胞瘤的 KDM6B 靶向治疗提供了依据。
