Bromodomain and extra terminal containing protein (BET) family proteins, which include Brd2, Brd3, Brd4, and BrdT, are known for epigenetic readers that recognize acetylated lysine on histone or non-histone proteins via their two bromodomains. These BET proteins are involved in cell proliferation, d...
Bromodomain and extra terminal containing protein (BET) family proteins, which include Brd2, Brd3, Brd4, and BrdT, are known for epigenetic readers that recognize acetylated lysine on histone or non-histone proteins via their two bromodomains. These BET proteins are involved in cell proliferation, development of haematological malignancies, and various solid tumors. Recently, BET inhibitors, such as JQ1 or PFI-1 have emerged as potential cancer therapeutics due to their powerful anti-tumor effects. Despite the role of the BET inhibitors as anti-tumor agents, the molecular mechanism is poorly understood. In this study, I found that BET inhibitors effectively repressed cell growth and migration activity on HCT116 cell lines in a p53-independent manner. As a result of a cellular proliferation and a cellular apoptosis assay, BET inhibitors have an effect to repress cell proliferation and migration, but they don’t induce apoptosis. Also, I analyzed the progression of cell cycle by conducting Propidium Iodide (PI) staining. The results showed that the BET inhibitors-treated cells were arrested on G1/S phase. To address the molecular mechanism underlying these effects, which may be occurring due to the inhibition of BET proteins, I analyzed the change of gene expression related to G1/S phase arrest. The results showed that BET inhibitors induced the elevated expression of p21, whereas they reduced the expression of E2F1 target genes, which included C-MYC. Consistently, down-regulated Rb phosphorylation by BET inhibitors caused E2F1 inactivation. Moreover, I showed that BET proteins were recruited by E2F1 to the regulatory regions of its target genes through their tandem bromodomains, which interacted with acetylated K5/12 on histone H4 (H4K5/12Ac). In turn, BET proteins increased the active histone markers and decreased the repressive histone markers, but these effects were reversed by BET inhibitors. Overall, this study suggests that the inhibition of BET proteins may play a critical role to suppress the tumor growth through regulation of the histone modifications on the promoter of E2F1 target genes such as C-MYC.
Bromodomain and extra terminal containing protein (BET) family proteins, which include Brd2, Brd3, Brd4, and BrdT, are known for epigenetic readers that recognize acetylated lysine on histone or non-histone proteins via their two bromodomains. These BET proteins are involved in cell proliferation, development of haematological malignancies, and various solid tumors. Recently, BET inhibitors, such as JQ1 or PFI-1 have emerged as potential cancer therapeutics due to their powerful anti-tumor effects. Despite the role of the BET inhibitors as anti-tumor agents, the molecular mechanism is poorly understood. In this study, I found that BET inhibitors effectively repressed cell growth and migration activity on HCT116 cell lines in a p53-independent manner. As a result of a cellular proliferation and a cellular apoptosis assay, BET inhibitors have an effect to repress cell proliferation and migration, but they don’t induce apoptosis. Also, I analyzed the progression of cell cycle by conducting Propidium Iodide (PI) staining. The results showed that the BET inhibitors-treated cells were arrested on G1/S phase. To address the molecular mechanism underlying these effects, which may be occurring due to the inhibition of BET proteins, I analyzed the change of gene expression related to G1/S phase arrest. The results showed that BET inhibitors induced the elevated expression of p21, whereas they reduced the expression of E2F1 target genes, which included C-MYC. Consistently, down-regulated Rb phosphorylation by BET inhibitors caused E2F1 inactivation. Moreover, I showed that BET proteins were recruited by E2F1 to the regulatory regions of its target genes through their tandem bromodomains, which interacted with acetylated K5/12 on histone H4 (H4K5/12Ac). In turn, BET proteins increased the active histone markers and decreased the repressive histone markers, but these effects were reversed by BET inhibitors. Overall, this study suggests that the inhibition of BET proteins may play a critical role to suppress the tumor growth through regulation of the histone modifications on the promoter of E2F1 target genes such as C-MYC.
주제어
#BET proteins PFI-1 JQ1 p21 E2F1 Histone modification
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