Matches in SemOpenAlex for { <https://semopenalex.org/work/W3040657839> ?p ?o ?g. }
- W3040657839 abstract "ABSTRACT 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." @default.
- W3040657839 created "2020-07-10" @default.
- W3040657839 creator A5009712417 @default.
- W3040657839 creator A5029866856 @default.
- W3040657839 creator A5030567099 @default.
- W3040657839 creator A5048752992 @default.
- W3040657839 creator A5048929218 @default.
- W3040657839 creator A5054639047 @default.
- W3040657839 creator A5057538695 @default.
- W3040657839 creator A5058411760 @default.
- W3040657839 creator A5063204371 @default.
- W3040657839 creator A5064409505 @default.
- W3040657839 creator A5066629883 @default.
- W3040657839 creator A5079848726 @default.
- W3040657839 creator A5081305115 @default.
- W3040657839 date "2020-07-03" @default.
- W3040657839 modified "2023-10-16" @default.
- W3040657839 title "KDM6B promotes oncogenic CDK4/6-pRB-E2F pathway via maintaining enhancer activation in high-risk neuroblastoma" @default.
- W3040657839 cites W1162737367 @default.
- W3040657839 cites W1907727697 @default.
- W3040657839 cites W1969341584 @default.
- W3040657839 cites W1970246059 @default.
- W3040657839 cites W1970592702 @default.
- W3040657839 cites W1971578941 @default.
- W3040657839 cites W1972076975 @default.
- W3040657839 cites W1973062929 @default.
- W3040657839 cites W1980255776 @default.
- W3040657839 cites W1981361342 @default.
- W3040657839 cites W1988294855 @default.
- W3040657839 cites W1989617311 @default.
- W3040657839 cites W1991199800 @default.
- W3040657839 cites W1992708996 @default.
- W3040657839 cites W1996213181 @default.
- W3040657839 cites W1996477655 @default.
- W3040657839 cites W2004608668 @default.
- W3040657839 cites W2004966039 @default.
- W3040657839 cites W2008735740 @default.
- W3040657839 cites W2021341670 @default.
- W3040657839 cites W2022495797 @default.
- W3040657839 cites W2022930470 @default.
- W3040657839 cites W2024531852 @default.
- W3040657839 cites W2025856640 @default.
- W3040657839 cites W2035151755 @default.
- W3040657839 cites W2041535798 @default.
- W3040657839 cites W2057364464 @default.
- W3040657839 cites W2061468315 @default.
- W3040657839 cites W2062307771 @default.
- W3040657839 cites W2062927905 @default.
- W3040657839 cites W2080585376 @default.
- W3040657839 cites W2086554513 @default.
- W3040657839 cites W2095296988 @default.
- W3040657839 cites W2102619694 @default.
- W3040657839 cites W2103441770 @default.
- W3040657839 cites W2104490470 @default.
- W3040657839 cites W2108234281 @default.
- W3040657839 cites W2109378990 @default.
- W3040657839 cites W2117757143 @default.
- W3040657839 cites W2118071133 @default.
- W3040657839 cites W2119279070 @default.
- W3040657839 cites W2122583405 @default.
- W3040657839 cites W2128151873 @default.
- W3040657839 cites W2130410032 @default.
- W3040657839 cites W2130925781 @default.
- W3040657839 cites W2133382697 @default.
- W3040657839 cites W2134409560 @default.
- W3040657839 cites W2135030836 @default.
- W3040657839 cites W2137526110 @default.
- W3040657839 cites W2139558183 @default.
- W3040657839 cites W2141287548 @default.
- W3040657839 cites W2147524392 @default.
- W3040657839 cites W2150148604 @default.
- W3040657839 cites W2153019757 @default.
- W3040657839 cites W2157009395 @default.
- W3040657839 cites W2157495337 @default.
- W3040657839 cites W2157789221 @default.
- W3040657839 cites W2169484696 @default.
- W3040657839 cites W2170846478 @default.
- W3040657839 cites W2171439874 @default.
- W3040657839 cites W2171808845 @default.
- W3040657839 cites W2175853567 @default.
- W3040657839 cites W2175970000 @default.
- W3040657839 cites W2219817965 @default.
- W3040657839 cites W2220553089 @default.
- W3040657839 cites W2346893706 @default.
- W3040657839 cites W2471978271 @default.
- W3040657839 cites W2522404881 @default.
- W3040657839 cites W2531255230 @default.
- W3040657839 cites W2594764564 @default.
- W3040657839 cites W2612084614 @default.
- W3040657839 cites W2616897169 @default.
- W3040657839 cites W2731219769 @default.
- W3040657839 cites W2733464733 @default.
- W3040657839 cites W2766707799 @default.
- W3040657839 cites W2768977980 @default.
- W3040657839 cites W2774087343 @default.
- W3040657839 cites W2774699268 @default.
- W3040657839 cites W2776802713 @default.
- W3040657839 cites W2788562722 @default.
- W3040657839 cites W2793601014 @default.
- W3040657839 cites W2794299014 @default.