{"doi":"10.1101/2020.07.02.184986","title":"KDM6B promotes activation of the oncogenic CDK4/6-pRB-E2F pathway by maintaining enhancer activity in MYCN-amplified neuroblastoma","abstract":"ABSTRACT 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.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2020,"id":123858,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":3,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9496,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":567409,"name":"Jie Fang","orcid":"0000-0001-6119-1195","position":1,"is_corresponding":false},{"id":55234,"name":"Hongjian Jin","orcid":"0000-0003-3833-7170","position":2,"is_corresponding":false},{"id":267013,"name":"Beisi Xu","orcid":"0000-0003-0099-858X","position":3,"is_corresponding":false},{"id":381369,"name":"Shivendra V. Singh","orcid":"0000-0002-4153-8056","position":4,"is_corresponding":false},{"id":568063,"name":"Anoushka Mullasseril","orcid":null,"position":5,"is_corresponding":false},{"id":567410,"name":"Victoria Jones","orcid":"0009-0003-1202-9257","position":6,"is_corresponding":false},{"id":381370,"name":"Ahmed Abu‐Zaid","orcid":"0000-0003-2286-2181","position":7,"is_corresponding":false},{"id":567411,"name":"Xinyu von Buttlar","orcid":"0000-0001-6131-8555","position":8,"is_corresponding":false},{"id":382288,"name":"Bailey Cooke","orcid":null,"position":9,"is_corresponding":false},{"id":567412,"name":"Dongli Hu","orcid":"0000-0001-5716-2084","position":10,"is_corresponding":false},{"id":567413,"name":"Jason M. Shohet","orcid":"0000-0001-8059-3771","position":11,"is_corresponding":false},{"id":381384,"name":"Andrew J. Murphy","orcid":"0000-0001-6747-0355","position":12,"is_corresponding":false},{"id":356186,"name":"Andrew M. Davidoff","orcid":"0000-0001-7900-2794","position":13,"is_corresponding":false},{"id":107683,"name":"Jun J. Yang","orcid":"0000-0002-0770-9659","position":14,"is_corresponding":false},{"id":568062,"name":"Alexandra D’Oto","orcid":null,"position":0,"is_corresponding":true}],"reference_count":113,"raw_metadata":null,"created_at":"2026-07-18T23:15:03.403566Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}