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Converged DNA Damage Response Renders Human Hepatocellular Carcinoma Sensitive to CDK7 Inhibition
Guiqin Xie1,2, Ailin Zhu1, Xinbin Gu1,2
1Department of Oral Pathology, Howard University, 600 W. Street NW, Washington, DC 20059, USA.
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.
Insights
Hepatocellular carcinoma (HCC) cells are sensitive to CDK7 inhibitor THZ1, which triggers MYC-related apoptosis and DNA damage. Overexpressing MYC enhances THZ1
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Hepatocellular carcinoma (HCC) is a deadly cancer with high mortality.
- Cyclin-dependent kinase 7 (CDK7) inhibition shows promise for HCC therapy, but mechanisms are unclear.
- Understanding CDK7's role is crucial for developing effective HCC treatments.
Purpose of the Study:
- To elucidate the molecular mechanisms underlying the therapeutic efficacy of CDK7 inhibition in HCC.
- To investigate the role of MYC in THZ1-induced apoptosis and DNA damage in HCC cells.
- To explore THZ1 as a potential therapeutic strategy for HCC.
Main Methods:
- Treatment of HCC cell lines (HepG2, Hep3B, SK-Hep-1) with the CDK7 inhibitor THZ1.
- Assessment of tumor growth and weight in mouse models.
- Cell cycle analysis and apoptosis assays.
- Overexpression of MYC in HCC cells to study its effect on THZ1 sensitivity.
- Evaluation of DNA damage response following THZ1 treatment.
Main Results:
- HCC cell lines demonstrated high susceptibility to THZ1.
- THZ1 reduced tumor growth and weight in mouse models.
- THZ1 induced cell cycle arrest and MYC-related apoptosis.
- Overexpression of MYC sensitized HCC cells to THZ1-induced apoptosis, particularly in S and G2/M phases.
- THZ1 treatment led to increased DNA damage, which was further enhanced by MYC overexpression.
Conclusions:
- CDK7 inhibition by THZ1, combined with MYC-promoted cell cycle progression, enhances HCC sensitivity to DNA-damage-induced cell death.
- These findings suggest a novel therapeutic strategy targeting CDK7 and MYC pathways in HCC treatment.
- THZ1 represents a promising therapeutic agent for hepatocellular carcinoma.
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