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Epigenetic reader BRD4 inhibition as a therapeutic strategy to suppress E2F2-cell cycle regulation circuit in liver cancer
- Source :
- Oncotarget
- Publication Year :
- 2016
-
Abstract
- Deregulation of the epigenome component affects multiple pathways in the cancer phenotype since the epigenome acts at the pinnacle of the hierarchy of gene expression. Pioneering work over the past decades has highlighted that targeting enzymes or proteins involved in the epigenetic regulation is a valuable approach to cancer therapy. Very recent results demonstrated that inhibiting the epigenetic reader BRD4 has notable efficacy in diverse cancer types. We investigated the potential of BRD4 as a therapeutic target in liver malignancy. BRD4 was overexpressed in three different large cohort of hepatocellular carcinoma (HCC) patients as well as in liver cancer cell lines. BRD4 inhibition by JQ1 induced anti-tumorigenic effects including cell cycle arrest, cellular senescence, reduced wound healing capacity and soft agar colony formation in liver cancer cell lines. Notably, BRD4 inhibition caused MYC-independent large-scale gene expression changes in liver cancer cells. Serial gene expression analyses with SK-Hep1 liver cancer cells treated with JQ1 to delineate the key player of BRD4 inhibition identified E2F2 as the first line of downstream direct target of BRD4. Further experiments including chromatin immunoprecipitation (ChIP) assay and loss of function study confirmed E2F2 as key player of BRD4 inhibition. Overexpressed E2F2 is a crucial center of cell cycle regulation and high expression of E2F2 is significantly associated with poor prognosis of HCC patients. Our findings reveal BRD4-E2F2-cell cycle regulation as a novel molecular circuit in liver cancer and provide a therapeutic strategy and innovative insights for liver cancer therapies.
- Subjects :
- 0301 basic medicine
Cell cycle checkpoint
Carcinoma, Hepatocellular
JQ1
Cell Cycle Proteins
Bioinformatics
epigenetic components
BET protein
Epigenesis, Genetic
03 medical and health sciences
hepatocellular carcinoma (HCC)
E2F2 Transcription Factor
E2F
Cell Line, Tumor
medicine
Humans
Epigenetics
Cell Proliferation
Cell growth
business.industry
Liver Neoplasms
Cancer
Nuclear Proteins
Epigenome
Azepines
Cell Cycle Checkpoints
Hep G2 Cells
Cell cycle
Triazoles
medicine.disease
030104 developmental biology
Oncology
Cancer research
Liver cancer
business
Transcription Factors
Research Paper
Subjects
Details
- ISSN :
- 19492553
- Volume :
- 7
- Issue :
- 22
- Database :
- OpenAIRE
- Journal :
- Oncotarget
- Accession number :
- edsair.doi.dedup.....ec4c2ecc2d0a5833a3b58c28b5b64f17