Abstract
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.
Highlights
The H3K27me2/me[3] histone demethylase KDM6B is essential to neuroblastoma cell survival
We found that levels of KDM6B expression, but not KDM6A or UTY, in neuroblastoma cell lines were among the highest, across 40 different cancer lineages (Supplementary Fig. 1a)
Despite one recent study suggesting that KDM6B might be tumor suppressive in neuroblastoma[67], we and others have found that KDM6B plays an important role in MYC-driven tumorigenesis and that pharmacologically targeting KDM6B by the small molecule GSK-J4 is therapeutically efficacious in multiple tumor models[14,27,68,69,70,71], including high-risk neuroblastoma[43]
Summary
The H3K27me2/me[3] histone demethylase KDM6B is essential to neuroblastoma cell survival. 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 CDK4/6pRB-E2F pathway in neuroblastoma cells via H3K27me3-dependent enhancer-promoter interactions, providing a rationale to target KDM6B for high-risk neuroblastoma. Neuroblastoma, the most common extra-cranial solid tumor in children, arises as a result of blocked differentiation of neural crest precursors (NCCs) during development of the sympathetic nervous system[19,20] This aggressive malignancy accounts for 15% of cancer-related deaths in children[21]. Our previous study demonstrated that the histone demethylase KDM4B regulates MYC activity and promotes tumor growth and maintenance of neuroblastoma[26]. Using chemical genetic and epigenetic approaches, we show that KDM6B is involved in regulation of the key oncogenic CDK4/6-pRB-E2F pathway and expression of both
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