{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Xie G"],"funding":["NIDCR NIH HHS","NCI NIH HHS","National Institutes of Health","NIH HHS"],"pagination":["1714"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC8996977"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["14(7)"],"pubmed_abstract":["Hepatocellular carcinoma (HCC) is a lethal malignancy with high mortality. The inhibition of cyclin-dependent kinase 7 (CDK7) activity has shown therapeutic efficacy in HCC. However, the underlying molecular mechanisms remain elusive. Here, we show that three HCC lines, HepG2, Hep3B, and SK-Hep-1, were highly susceptible to the CDK7 inhibitor THZ1. In mouse models, THZ1 effectively reduced HepG2 tumor growth and tumor weight. THZ1 arrested cell cycle and triggered MYC-related apoptosis in HepG2. To evaluate how MYC protein levels affected THZ1-induced apoptotic cell death, we overexpressed MYC in HepG2 and found that exogenously overexpressed MYC promoted cell cycle progression and increased cells in the S phase. THZ1 drastically engendered the apoptosis of MYC-overexpressing HepG2 cells in the S and G2/M phases. Importantly, transcription-inhibition-induced apoptosis is associated with DNA damage, and exogenous MYC expression further enhanced the THZ1-induced DNA damage response in MYC-overexpressing HepG2 cells. Consistently, in the HepG2 xenografts, THZ1 treatment was associated with DNA-damage-induced cell death. Together, our data indicate that the converged effect of MYC-promoted cell cycle progression and CDK7 inhibition by THZ1 confers the hypersensitivity of HCC to DNA-damage-induced cell death. Our findings may suggest a new therapeutic strategy of THZ1 against HCC."],"journal":["Cancers"],"pubmed_title":["Converged DNA Damage Response Renders Human Hepatocellular Carcinoma Sensitive to CDK7 Inhibition."],"pmcid":["PMC8996977"],"funding_grant_id":["R15DE025138, R25DE025778, and R03DE030227","R15 DE025138","R03 DE030227","R25 DE025778","P50 CA098252"],"pubmed_authors":["Xie G","Gu X","Zhu A"],"additional_accession":[]},"is_claimable":false,"name":"Converged DNA Damage Response Renders Human Hepatocellular Carcinoma Sensitive to CDK7 Inhibition.","description":"Hepatocellular carcinoma (HCC) is a lethal malignancy with high mortality. The inhibition of cyclin-dependent kinase 7 (CDK7) activity has shown therapeutic efficacy in HCC. However, the underlying molecular mechanisms remain elusive. Here, we show that three HCC lines, HepG2, Hep3B, and SK-Hep-1, were highly susceptible to the CDK7 inhibitor THZ1. In mouse models, THZ1 effectively reduced HepG2 tumor growth and tumor weight. THZ1 arrested cell cycle and triggered MYC-related apoptosis in HepG2. To evaluate how MYC protein levels affected THZ1-induced apoptotic cell death, we overexpressed MYC in HepG2 and found that exogenously overexpressed MYC promoted cell cycle progression and increased cells in the S phase. THZ1 drastically engendered the apoptosis of MYC-overexpressing HepG2 cells in the S and G2/M phases. Importantly, transcription-inhibition-induced apoptosis is associated with DNA damage, and exogenous MYC expression further enhanced the THZ1-induced DNA damage response in MYC-overexpressing HepG2 cells. Consistently, in the HepG2 xenografts, THZ1 treatment was associated with DNA-damage-induced cell death. Together, our data indicate that the converged effect of MYC-promoted cell cycle progression and CDK7 inhibition by THZ1 confers the hypersensitivity of HCC to DNA-damage-induced cell death. Our findings may suggest a new therapeutic strategy of THZ1 against HCC.","dates":{"release":"2022-01-01T00:00:00Z","publication":"2022 Mar","modification":"2026-05-07T03:08:25.892Z","creation":"2025-02-19T01:10:45.948Z"},"accession":"S-EPMC8996977","cross_references":{"pubmed":["35406486"],"doi":["10.3390/cancers14071714"]}}