Histone acetyltransferase p300/CBP inhibitor C646 blocks the survival and invasion pathways of gastric cancer cell lines

Abstract

The histone acetyltransferases (HATs) adenovirus E1A-associated protein (p300) and CREB binding protein (CBP) serve as coactivators during a diverse assortment of cellular processes. In the present study, p300 and CBP were highly expressed in 5 gastric cancer (GC) cell lines (SGC‑7901, MKN45, MGC-803, BGC-823 and KATO III) compared with human normal gastric epithelial cell line (GES-1). C646, a selective inhibitor of p300 and CBP, inhibited cell viability and cell cycle and promoted cell apoptosis in all 5 GC cell lines. In addition, C646 suppressed the migration and invasion capability of the GC cell lines, except for the middle-differentiated SGC-7901 cell line. Furthermore, we detected the differential expression of corresponding oncogenic signalling molecules, such as c-Met, Akt, Bcl-2, Bax, cyclin D1, MMP7 and MMP9, in GC cells following C646 treatment. In conclusion, our results suggest that C646 inhibits the acetylation of histone H3 via inactivation of p300 and CBP, resulting in antineoplastic effects toward GC cells. Thus, the selective HAT inhibitor C646 could be a promising antitumour reagent for GC treatment.

Molecular Structure, Binding Affinity, and Biological Activity in the Epigenome

“…Higher doses (> 10 µmol/L) of C646 resulted in a stronger inhibition of cell proliferation on gastric cancer cell lines, than on normal gastric epithelial cells. In addition, it increased the number of apoptotic cells in gastric cancer cell lines and reduced migration and invasion potential [162]. C646 treatment reduced the acetylation of histone H3 in both gastric carcinoma cells and normal gastric epithelial cells.…”

“…A cell proliferation assay, based on the measurement of optical density was used to study the effects of a small molecule inhibitor on gastric cancer [162] and gastrointestinal stromal tumor cell lines [163]. C646, a HAT inhibitor (see Section 1), inhibits the enzymatic activities of p300 and CREB binding protein (CBP).…”

“…C646, a HAT inhibitor (see Section 1), inhibits the enzymatic activities of p300 and CREB binding protein (CBP). These HATs control the acetylation of histone H3, their inhibition exerts antineoplastic effects on various cancer cell lines [162,163]. In two studies [162,163], it was tested whether their inhibition provides beneficial effects against two types of malignant diseases of the gastrointestinal tract.…”

“…These HATs control the acetylation of histone H3, their inhibition exerts antineoplastic effects on various cancer cell lines [162,163]. In two studies [162,163], it was tested whether their inhibition provides beneficial effects against two types of malignant diseases of the gastrointestinal tract. In the first study [162], CBP and p300 enzymes were overexpressed in five gastric cancer cell lines.…”

“…In two studies [162,163], it was tested whether their inhibition provides beneficial effects against two types of malignant diseases of the gastrointestinal tract. In the first study [162], CBP and p300 enzymes were overexpressed in five gastric cancer cell lines. The control was a normal gastric cell line.…”