Expression of hMOF, but not HDAC4, is responsible for the global histone H4K16 acetylation in gastric carcinoma

Abstract

Increasing evidence suggests that the alteration of global histone H4K16 acetylation (H4K16ac) may be involved in several types of cancer. It is known that the global histone H4K16ac level in cells is controlled by several enzymes including histone acetyltransferases (HATs) and histone deacetylases (HDACs). We report in detail which particular enzyme is responsible for global reduction of histone H4K16ac in gastric cancer. Our study included 156 frozen tissue samples of primary diagnosed gastric cancer tissues and matched adjacent or normal tissues, and the gastric cancer cells SGC-7901 and MGC-803. The reverse transcription polymerase chain reaction (RT-PCR), western blot, transient transfection and siRNA knockdown approaches were used. Statistical analysis of the qRT-PCR data revealed that a significant reduction (>2-fold decreased) of hMOF expression in gastric cancer tissues in 81% (42/52) of patients. In patients with gastric cancer, downregulation of hMOF was connected to gastric cancer and tissues with pT2-T4 tumor status, lymph node metastasis and distant metastasis. Overall survival rates revealed a significant difference between the low- and high- hMOF expression groups. However, there was no significant difference by age, gender and cell differentiation. In SGC-7901 and MGC-803 gastric cancer cells, as expected, low expression of hMOF and decreased global histone H4K16ac were observed. Although we did not obtained a statistically significant high-level of HDAC4 in tumor tissues, increased HDAC4 in both gastric cancer cell lines was detected. Therefore, overexpression of hMOF and knockdown of HDAC4 experiments were carried out to investigate the potential coordinating role between hMOF and HDAC4 on global histone H4K16ac in gastric cancer. Overexpression of hMOF increased global H4K16ac in cells, however, no obvious increase of global H4K16ac in HDAC4 knockdown MGC-803 cells was observed. Histone acetyltransferase hMOF and global histone H4K16ac status might be involved in gastric cancer tumorigenic pathways. hMOF, but not HDAC4, is mainly responsible for global histone H4K16ac acetylation in gastric cancer cells.