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Hypoxia-inducible factor-1 (HIF-1) is a transcription factor which plays a critical role in several biochemical pathways, and consists of oxygen-dependent alpha (α) and a constitutively expressed beta (β) subunit. Under hypoxic conditions, HIF-1α is stabilized and forms a complex with β subunit and this complex is associated with cancer progression. HIF-1α activity is mainly regulated by its transcriptional co-activator p300 which has histone acetyl-transferase (HAT) activity. p300 HAT activity is very crucial for p300 auto-acetylation and subsequently its interaction with its partner molecule HIF-1α as well as proapoptotic protein p53. p300 is a multi-domain protein and CH1 domain of p300 is the interacting partner of the C-terminal domain (CTD) of HIF-1α as well as p53. Several p300 HAT inhibitors are reported to suppress p300 auto-acetylation which inhibits its interaction with associated partners. We demonstrated that the p300 HAT inhibitor CTK7A down-regulated p300 auto-acetylation, HIF-1α accumulation as well as activity in gastric cancer cell lines. Protein-protein interaction and molecular docking studies revealed a significant decrease in the binding energy of full-length p300 as well as p300-CH1 and HIF-1α-CTD complex in presence of CTK7A. Further, SwissADME, evaluates the drug-likeliness property of CTK7A by analyzing its lipophilicity, size, polarity, solubility, saturation, and flexibility. Our in vitro and in silico data support reduced HIF-1α-p300 interaction in the presence of CTK7A. Hence, CTK7A might be playing a crucial role in down-regulating HIF-1α activity and can be a prospective anticancer drug. |
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