{"doi":"10.1101/2024.12.06.626451","title":"Chemical perturbations impacting histone acetylation govern colorectal cancer differentiation","abstract":"Dysregulated epigenetic programs that restrict differentiation, reactivate fetal genes, and confer phenotypic plasticity are critical to colorectal cancer (CRC) development. By screening a small molecule library targeting epigenetic regulators using our dual reporter system, we found that inhibiting histone deacetylase (HDAC) 1/2 promotes CRC differentiation and anti-tumor activity. Comprehensive biochemical, chemical, and genetic experiments revealed that on-target blockade of the HDAC1/2 catalytic domain mediated the differentiated phenotype. Unbiased profiling of histone posttranslational modifications induced by HDAC1/2 inhibition nominated acetylation of specific histone lysine residues as potential regulators of differentiation. Genome-wide assessment of implicated marks indicated that H3K27ac gains at HDAC1/2-bound regions associated with open chromatin and upregulation of differentiation genes upon HDAC1/2 inhibition. Disrupting H3K27ac by degrading acetyltransferase EP300 rescued HDAC1/2 inhibitor-mediated differentiation of a patient-derived CRC model using single cell RNA-sequencing. Genetic screens revealed that DAPK3 contributes to CRC differentiation induced by HDAC1/2 inhibition. These results highlight the importance of specific chemically targetable histone modifications in governing cancer cell states and epigenetic reprogramming as a therapeutic strategy in CRC.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2024,"id":489375,"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":2,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9536,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":60541,"name":"Zhixin Li","orcid":"0000-0001-9962-3942","position":1,"is_corresponding":false},{"id":986319,"name":"Khoa Doan","orcid":"0000-0002-7329-3495","position":2,"is_corresponding":false},{"id":645038,"name":"Sándor Spisák","orcid":"0000-0002-7834-4642","position":3,"is_corresponding":false},{"id":1334268,"name":"Akhouri Kishore Raghawan","orcid":"0000-0002-1628-5974","position":4,"is_corresponding":false},{"id":640527,"name":"Qi Liu","orcid":"0009-0002-0475-3424","position":5,"is_corresponding":false},{"id":1040725,"name":"Priscilla Liow","orcid":"0000-0002-4871-9423","position":6,"is_corresponding":false},{"id":1334269,"name":"Sunwoo Lee","orcid":"0000-0003-2806-3268","position":7,"is_corresponding":false},{"id":597257,"name":"David J. Chen","orcid":"0000-0003-0046-6903","position":8,"is_corresponding":false},{"id":648035,"name":"Pratyusha Bala","orcid":"0000-0001-7686-4700","position":9,"is_corresponding":false},{"id":648036,"name":"Pranshu Sahgal","orcid":"0000-0002-9857-3987","position":10,"is_corresponding":false},{"id":986317,"name":"Daulet Aitymbayev","orcid":"0000-0001-7277-2884","position":11,"is_corresponding":false},{"id":567787,"name":"Jennifer S. Thalappillil","orcid":"0000-0002-4860-3033","position":12,"is_corresponding":false},{"id":664949,"name":"Malvina Papanastasiou","orcid":"0000-0003-3378-6612","position":13,"is_corresponding":false},{"id":1234587,"name":"William Hawkins","orcid":null,"position":14,"is_corresponding":false},{"id":2226,"name":"Steven A. Carr","orcid":"0000-0002-7203-4299","position":15,"is_corresponding":false},{"id":231716,"name":"Haeseong Park","orcid":"0000-0002-3430-8463","position":16,"is_corresponding":false},{"id":241905,"name":"James M. Cleary","orcid":"0000-0001-7213-3951","position":17,"is_corresponding":false},{"id":260598,"name":"Jun Qi","orcid":"0000-0002-1461-3356","position":18,"is_corresponding":false},{"id":313833,"name":"Nilay S. Sethi","orcid":"0000-0002-3748-7559","position":19,"is_corresponding":false},{"id":1188445,"name":"Pornlada Likasitwatanakul","orcid":"0000-0002-9689-3231","position":0,"is_corresponding":true}],"reference_count":133,"raw_metadata":null,"created_at":"2026-07-19T02:08:23.929823Z","pmid":"39713466","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":[]}