4-Phenybutyric acid promotes gastric cancer cell migration via histone deacetylase inhibition-mediated HER3/HER4 up-regulation.

ABSTRACT

Dysregulation of histone acetylation plays an important role in tumor development. Histone acetylation regulates gene transcription and expression, which is reversibly regulated by histone acetyltransferase (HAT) and histone deacetylase (HDAC). As an HDAC inhibitor, 4-phenylbutyric acid (4-PBA) can increase histone acetylation levels by inhibiting HDAC activity. While 4-PBA inhibits proliferation of tumor cells in vitro, clinical trials have failed to show benefits of 4-PBA for refractory solid tumors. Here, we found that 4-PBA could enhance the migration capacity of gastric cancer cells. Upregulation of HER3/HER4 and activation of HER3/HER4-ERK pathway was shown to be involved in 4-PBA-induced gastric cancer cell migration. Knockdown of HER3/HER4 blocked HER3/HER4-ERK activation and partially prevented 4-PBA-induced cell migration. Consistently, the ERK inhibitor PD98059 also partially prevented 4-PBA-induced cell migration. Moreover, enhanced levels of acetyl-histones were detected following 4-PBA-treatment, and histone3 acetylation in promoter regions of HER3 and HER4 were confirmed by ChIP. These results demonstrate that 4-PBA promotes gastric cancer cells migration through upregulation of HER3/HER4 subsequent to increased levels of acetyl-histone and activation of ERK signaling. These novel findings provide important considerations for the use of 4-PBA in cancer therapeutics.