RT Journal Article
SR Electronic
T1 KDM6B promotes activation of the oncogenic CDK4/6-pRB-E2F pathway by maintaining enhancer activity in MYCN-amplified neuroblastoma
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2020.07.02.184986
DO 10.1101/2020.07.02.184986
A1 Alexandra D’Oto
A1 Jie Fang
A1 Hongjian Jin
A1 Beisi Xu
A1 Shivendra Singh
A1 Anoushka Mullasseril
A1 Victoria Jones
A1 Ahmed Abu-Zaid
A1 Xinyu von Buttlar
A1 Bailey Cooke
A1 Dongli Hu
A1 Jason Shohet
A1 Andrew J Murphy
A1 Andrew M Davidoff
A1 Jun Yang
YR 2021
UL http://biorxiv.org/content/early/2021/10/26/2020.07.02.184986.abstract
AB The H3K27me2/me3 histone demethylase KDM6B is over-expressed in neuroblastoma and is 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 downregulates the pRB-E2F transcriptome and MYCN expression. Chemical genetic analyses show that high expression of the E2F transcriptome is positively correlated with sensitivity of cancer cells to GSK-J4. Mechanistically, 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 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.