PT - JOURNAL ARTICLE AU - Alexandra D’Oto AU - Jie Fang AU - Hongjian Jin AU - Beisi Xu AU - Shivendra Singh AU - Anoushka Mullasseril AU - Victoria Jones AU - Xinyu von Buttlar AU - Bailey Cooke AU - Dongli Hu AU - Jason Shohet AU - Andrew J Murphy AU - Andrew M Davidoff AU - Jun Yang TI - KDM6B promotes oncogenic CDK4/6-pRB-E2F pathway via maintaining enhancer activation in high-risk neuroblastoma AID - 10.1101/2020.07.02.184986 DP - 2020 Jan 01 TA - bioRxiv PG - 2020.07.02.184986 4099 - http://biorxiv.org/content/early/2020/07/03/2020.07.02.184986.short 4100 - http://biorxiv.org/content/early/2020/07/03/2020.07.02.184986.full AB - The H3K27me2/me3 histone demethylase KDM6B is over-expressed in neuroblastoma and essential to neuroblastoma cell survival. While the KDM6B inhibitor, GSK-J4, has shown activity in in vitro and in vivo preclinical models, the mechanism of action remains poorly defined. We demonstrate that genetic and pharmacologic inhibition of KDM6B downregulate the pRB-E2F transcriptome and MYCN expression. Chemical genetics analyses show that a high E2F transcriptome is positively correlated with sensitivity of cancer cells to the KDM6 inhibitor GSK-J4. Mechanistically, inhibition of KDM6B activity reduces the chromatin accessibility of E2F target genes and MYCN. GSK-J4 alters distribution of H3K27me3 and broadly represses the enhancer mark H3K4me1, which may consequently disrupt the long-range chromatin interaction of E2F target genes. KDM6B inhibition phenocopies the transcriptome induced by the specific CDK4/6 inhibitor palbociclib. Overexpression of CDK4/6 or Rb1 knockout not only confers neuroblastoma cell resistance to palbociclib but also to GSK-J4. A gene signature targeted by KDM6B inhibition is associated with poor survival of patients with neuroblastoma regardless of the MYCN status. These data indicate that KDM6B activity 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.Competing Interest StatementThe authors have declared no competing interest.