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Co-overexpression of BRD4 and CDK7 promotes cell proliferation and predicts poor prognosis in HCC
Xinxiu Li1, Chuqian Zheng1, Yue Liu1
1Department of Medical Genetics and Developmental Biology, School of Medicine, The Key Laboratory of Developmental Genes and Human Diseases, Ministry of Education, Southeast University, Nanjing, China.
Abstract:
Aberrant expression of critical components of the trans-acting super-enhancers (SE) complex contributes to the continuous and robust transcription of oncogenes in human cancers. Small-molecule inhibitors targeting core-transcriptional components such as transcriptional bromodomain protein 4 (BRD4) and cyclin-dependent kinase 7 (CDK7) have been developed and are currently undergoing preclinical and clinical testing in several malignant cancers. By analysis of TCGA data and clinical specimens, we demonstrated that BRD4 and CDK7 were frequently overexpressed in human HCCs and were associated with the poor prognosis. Shorter survival and poorly differentiated histology were linked to high BRD4 or CDK7 expression levels. Interestingly, co-overexpression of BRD4 and CDK7 was a more unfavorable prognostic factor in HCC. Treatment with JQ1 or THZ1 alone exhibited an inhibitory impact on the proliferation of HCC cells, while JQ1 synergized with THZ1 showed a more pronounced suppression. Concurrently, a combined JQ1 and THZ1 treatment abolished the transcription of oncogenes ETV4, MYC, NFE2L2. Our study suggested that BRD4 and CDK7 coupled can be a valuable biomarker in HCC diagnosis and the combination of JQ1 and THZ1 can be a promising therapeutic treatment against HCC.
Insights
Aberrant expression of bromodomain protein 4 (BRD4) and cyclin-dependent kinase 7 (CDK7) correlates with poor prognosis in hepatocellular carcinoma (HCC). Combination therapy with BRD4 inhibitor JQ1 and CDK7 inhibitor THZ1 effectively suppresses HCC cell proliferation.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Genetics
Background:
- Aberrant super-enhancer (SE) complex transcription drives oncogene expression in cancers.
- Bromodomain protein 4 (BRD4) and cyclin-dependent kinase 7 (CDK7) are key SE components and therapeutic targets.
Purpose of the Study:
- To investigate the prognostic significance of BRD4 and CDK7 in hepatocellular carcinoma (HCC).
- To evaluate the therapeutic potential of combined BRD4 and CDK7 inhibition in HCC.
Main Methods:
- Analysis of The Cancer Genome Atlas (TCGA) data and clinical HCC specimens.
- Assessment of HCC cell proliferation inhibition by BRD4 inhibitor JQ1 and CDK7 inhibitor THZ1, alone and in combination.
- Evaluation of oncogene transcription (ETV4, MYC, NFE2L2) following combined treatment.
Main Results:
- BRD4 and CDK7 were frequently overexpressed in HCC, correlating with poor prognosis, shorter survival, and poorly differentiated histology.
- Co-overexpression of BRD4 and CDK7 presented a more unfavorable prognostic factor.
- Combined JQ1 and THZ1 treatment demonstrated synergistic suppression of HCC cell proliferation compared to single agents.
- Combined JQ1 and THZ1 treatment abolished the transcription of oncogenes ETV4, MYC, and NFE2L2.
Conclusions:
- BRD4 and CDK7 are valuable prognostic biomarkers for HCC.
- Combined inhibition of BRD4 and CDK7 using JQ1 and THZ1 represents a promising therapeutic strategy for HCC.
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