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.
Highlights
The function of the genome is determined by the epigenome, which consists of a record of the chemical changes to DNA and histone, and more broadly the compactness of the chromatin structure [1, 2]
We focused on the ED group, which more likely has direct targets of BRD4 inhibition; the group was greatly enriched in cancer related categories
E2F2 was up-regulated in three large cohorts of hepatocellular carcinoma (HCC) patients and several core genes were overexpressed in HCC tissue
Summary
The function of the genome is determined by the epigenome, which consists of a record of the chemical changes to DNA and histone, and more broadly the compactness of the chromatin structure [1, 2]. Chromatin structure which is a major determinant for gene expression potential is signed by the role of epigenome component [3]. There has been tremendous effort to develop small molecules which can target dysregulated epigenetic components. A number of epigenetic inhibitors have been developed; targeting DNA methyltransferase (DNMT) and histone deacetyltransferases (HDACs) have already been approved by the US Food and Drug Administration (FDA) [4, 6]. The first generation of bromodomain and extra-terminal domain (BET) protein inhibitors, JQ1 and I-BET, have www.impactjournals.com/oncotarget been developed and their feasibility in inhibiting reader molecules by interfering with protein-protein interaction has been established [7, 8]
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