Suppression of CBP/p300 induces growth inhibition and autophagy of hepatocellular carcinoma cells through regulation of EPHA2 by its super-enhancer acetylation.

CREB binding protein (CBP) and its homolog E1A binding protein p300 (p300) are crucial lysine acetyltransferases that have been shown to play key roles in various human malignancies. However, the precise functions and regulatory mechanisms of CBP/p300 in hepatocellular carcinoma (HCC) remain to be explored. Herein, we report that the expression levels of CBP and p300 are upregulated in HCC compared to normal tissues, and high CBP expression is associated with poor overall survival based on TCGA data. Combined knockdown of CBP and p300 or treatment with the CBP/p300 histone acetyltransferases (HAT) inhibitor A-485 reduces cell viability and promotes cell death in HCC cell lines. Additionally, inhibition of CBP/p300 activates autophagy, which mediates cell death in HCC cells. Mechanistically, the inhibition of CBP/p300 HAT activity attenuates H3K27ac at Ephrin type-A receptor 2 (EPHA2) super-enhancer and suppresses the expression of EPHA2. EPHA2 overexpression can partially rescue CBP/p300 HAT inhibition-mediated autophagy and loss of cell viability. These findings reveal a novel epigenetic mechanism of CBP/p300 in HCC and identify the CBP/p300 inhibitor A-485 as a promising therapeutic candidate for HCC.