{"doi":"10.1172/jci163592","title":"Superenhancer activation of KLHDC8A drives glioma ciliation and hedgehog signaling","abstract":"Glioblastoma ranks among the most aggressive and lethal of all human cancers. Self-renewing, highly tumorigenic glioblastoma stem cells (GSCs) contribute to therapeutic resistance and maintain cellular heterogeneity. Here, we interrogated superenhancer landscapes of primary glioblastoma specimens and patient-derived GSCs, revealing a kelch domain-containing gene, specifically Kelch domain containing 8A (KLHDC8A) with a previously unknown function as an epigenetically driven oncogene. Targeting KLHDC8A decreased GSC proliferation and self-renewal, induced apoptosis, and impaired in vivo tumor growth. Transcription factor control circuitry analyses revealed that the master transcriptional regulator SOX2 stimulated KLHDC8A expression. Mechanistically, KLHDC8A bound chaperonin-containing TCP1 (CCT) to promote the assembly of primary cilia to activate hedgehog signaling. KLHDC8A expression correlated with Aurora B/C Kinase inhibitor activity, which induced primary cilia and hedgehog signaling. Combinatorial targeting of Aurora B/C kinase and hedgehog displayed augmented benefit against GSC proliferation. Collectively, superenhancer-based discovery revealed KLHDC8A as what we believe to be a novel molecular target of cancer stem cells that promotes ciliogenesis to activate the hedgehog pathway, offering insights into therapeutic vulnerabilities for glioblastoma treatment.","journal":"Journal of Clinical Investigation","year":2022,"id":246890,"datarank":0.5416376868966337,"base_score":3.6109179126442243,"endowment":3.6109179126442243,"self_citation_contribution":0.5416376868966337,"citation_network_contribution":0.0,"self_endowment_contribution":0.5416376868966337,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":36,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.951,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":178168,"name":"Ryan C. Gimple","orcid":"0000-0002-7189-3243","position":1,"is_corresponding":false},{"id":883702,"name":"Xujia Wu","orcid":"0000-0002-6904-0778","position":2,"is_corresponding":false},{"id":88685,"name":"Briana C. Prager","orcid":"0000-0001-7173-6021","position":3,"is_corresponding":false},{"id":178167,"name":"Zhixin Qiu","orcid":"0000-0001-7103-8004","position":4,"is_corresponding":false},{"id":88682,"name":"Qiulian Wu","orcid":"0000-0002-7774-9576","position":5,"is_corresponding":false},{"id":426692,"name":"Vikas Daggubati","orcid":"0000-0002-9779-4614","position":6,"is_corresponding":false},{"id":883703,"name":"Aruljothi Mariappan","orcid":"0000-0001-5286-9806","position":7,"is_corresponding":false},{"id":883704,"name":"Jay Gopalakrishnan","orcid":"0000-0001-5907-3982","position":8,"is_corresponding":false},{"id":877524,"name":"Matthew R. Sarkisian","orcid":"0000-0002-0566-6480","position":9,"is_corresponding":false},{"id":88538,"name":"David R. Raleigh","orcid":"0000-0001-9299-8864","position":10,"is_corresponding":false},{"id":88695,"name":"Jeremy N. Rich","orcid":"0000-0001-7845-5302","position":11,"is_corresponding":false},{"id":236416,"name":"Derrick Lee","orcid":"0000-0001-7810-5572","position":0,"is_corresponding":true}],"reference_count":74,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T00:23:48.622830Z","pmid":"36394953","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":[]}