{"doi":"10.3389/fcell.2022.853652","title":"AZD5153, a Bivalent BRD4 Inhibitor, Suppresses Hepatocarcinogenesis by Altering BRD4 Chromosomal Landscape and Modulating the Transcriptome of HCC Cells","abstract":"BRD4, a chromatin modifier frequently upregulated in a variety of neoplasms including hepatocellular cancer (HCC), promotes cancer cell growth by activating oncogenes through its interaction with acetylated histone tails of nucleosomes. Here, we determined the anti-HCC efficacy of AZD5153, a potent bivalent BRD4 inhibitor, and elucidated its underlying molecular mechanism of action. AZD5153 treatment inhibited HCC cell proliferation, clonogenic survival and induced apoptosis in HCC cells. In vivo , AZD5153-formulated lipid nanoemulsions inhibited both orthotopic and subcutaneous HCCLM3 xenograft growth in NSG mice. Mapping of BRD4- chromosomal targets by ChIP-seq analysis identified the occupancy of BRD4 with the promoters, gene bodies, and super-enhancers of both mRNA and noncoding RNA genes, which were disrupted upon AZD5153 treatment. RNA-seq analysis of polyadenylated RNAs showed several BRD4 target genes involved in DNA replication, cell proliferation, and anti-apoptosis were repressed in AZD5153-treated HCC cells. In addition to known tumor-promoting genes, e.g., c- MYC , YAP1 , RAD51B , TRIB3 , SLC17A9 , JADE1 , we found that NAPRT , encoding a key enzyme for NAD + biosynthesis from nicotinic acid, was also suppressed in HCC cells by the BRD4 inhibitor. Interestingly, AZD5153 treatment upregulated NAMPT , whose product is the rate-limiting enzyme for NAD + synthesis from nicotinamide. This may explain why AZD5153 acted in concert with FK866, a potent NAMPT inhibitor, in reducing HCC cell proliferation and clonogenic survival. In conclusion, our results identified novel targets of BRD4 in the HCCLM3 cell genome and demonstrated anti-HCC efficacy of AZD5153, which was potentiated in combination with an NAMPT inhibitor.","journal":"Frontiers in Cell and Developmental Biology","year":2022,"id":252400,"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":23,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9563,"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":754262,"name":"Jimmy Chun‐Tien Kuo","orcid":null,"position":1,"is_corresponding":false},{"id":108228,"name":"Li Ding","orcid":"0000-0003-1517-2975","position":2,"is_corresponding":false},{"id":896449,"name":"Aaron B. Koenig","orcid":"0000-0002-2721-9454","position":3,"is_corresponding":false},{"id":741378,"name":"Alexander Pan","orcid":"0000-0001-5557-5619","position":4,"is_corresponding":false},{"id":395913,"name":"Pearlly S. Yan","orcid":"0000-0003-1965-4920","position":5,"is_corresponding":false},{"id":493715,"name":"Xue‐Feng Bai","orcid":"0000-0001-9476-8376","position":6,"is_corresponding":false},{"id":525090,"name":"Robert J. Lee","orcid":"0000-0002-5981-5867","position":7,"is_corresponding":false},{"id":382614,"name":"Kalpana Ghoshal","orcid":"0000-0002-8663-7787","position":8,"is_corresponding":false},{"id":669718,"name":"Cho-Hao Lin","orcid":"0000-0002-6165-904X","position":0,"is_corresponding":true}],"reference_count":61,"raw_metadata":null,"created_at":"2026-07-19T00:24:46.226372Z","pmid":"35399501","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":[]}