Inhibition of histone/lysine acetyltransferase activity kills CoCl2-treated and hypoxia-exposed gastric cancer cells and reduces their invasiveness

Abstract

Hypoxia enhances immortality and metastatic properties of solid tumors. Deregulation of histone acetylation has been associated with several metastatic cancers but its effect on hypoxic responses of cancer cells is not known. This study aimed at understanding the effectiveness of the hydrazinocurcumin, CTK7A, an inhibitor of p300 lysine/histone acetyltransferase (KAT/HAT) activity, in inducing apoptosis of gastric cancer cells (GCCs) exposed to cobalt chloride (CoCl₂), a hypoxia-mimetic chemical, or 1% O₂. Here, we show that CTK7A-induced hydrogen peroxide (H₂O₂) generation in CoCl₂-exposed and invasive gastric cancer cells (GCCs) leads to p38 MAPK-mediated Noxa expression and thereafter, mitochondrial apoptotic events. Noxa induction in normal immortalized gastric epithelial cells after CTK7A and hypoxia-exposure is remarkably less in comparison to similarly-treated GCCs. Moreover, hypoxia-exposed GCCs, which have acquired invasive properties, become apoptotic after CTK7A treatment to a significantly higher extent than normoxic cells. Thus, we show the potential of CTK7A in sensitizing hypoxic and metastatic GCCs to apoptosis induction.

Keywords: Apoptosis; CTK7A; Cancer metastasis; HAT; Hif1α; Hypoxia.