Zhu Lin, Yang Jiaxing, Zhao Linhong, Yu Xue, Wang Lingyao, Wang Fei, Cai Yong, Jin Jingji
School of Life Sciences, Jilin University, Changchun, Jilin 130012, P.R. China.
Department of Gastrointestinal Surgery, the First Bethune Hospital of Jilin University, Changchun, Jilin 130021, P.R. China.
Int J Oncol. 2015;46(6):2535-45. doi: 10.3892/ijo.2015.2956. Epub 2015 Apr 7.
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.
越来越多的证据表明，整体组蛋白H4K16乙酰化（H4K16ac）的改变可能与多种癌症相关。已知细胞中的整体组蛋白H4K16ac水平受多种酶调控，包括组蛋白乙酰转移酶（HATs）和组蛋白去乙酰化酶（HDACs）。我们详细报告了在胃癌中究竟是哪种特定酶导致了组蛋白H4K16ac的整体水平降低。我们的研究纳入了156份经病理确诊的原发性胃癌组织及其配对的癌旁或正常组织的冷冻样本，以及胃癌细胞SGC - 7901和MGC - 803。采用了逆转录聚合酶链反应（RT - PCR）、蛋白质免疫印迹法、瞬时转染和小干扰RNA（siRNA）敲低等方法。对qRT - PCR数据的统计分析显示，81%（42/52）的胃癌患者癌组织中hMOF表达显著降低（下降超过2倍）。在胃癌患者中，hMOF的下调与胃癌以及pT2 - T4肿瘤状态、淋巴结转移和远处转移的组织相关。总体生存率显示低hMOF表达组和高hMOF表达组之间存在显著差异。然而，在年龄、性别和细胞分化方面无显著差异。在SGC - 7901和MGC - 803胃癌细胞中，正如预期的那样，观察到hMOF低表达和整体组蛋白H4K16ac降低。虽然我们在肿瘤组织中未获得HDAC4高水平的统计学显著结果，但在两种胃癌细胞系中均检测到HDAC4增加。因此，进行了hMOF过表达和HDAC4敲低实验，以研究hMOF和HDAC4在胃癌整体组蛋白H4K16ac上的潜在协同作用。hMOF过表达增加了细胞中的整体H4K16ac，然而，在HDAC4敲低的MGC - 803细胞中未观察到整体H4K16ac明显增加。组蛋白乙酰转移酶hMOF和整体组蛋白H4K16ac状态可能参与胃癌的致瘤途径。在胃癌细胞中，主要是hMOF而非HDAC4负责整体组蛋白H4K16ac的乙酰化。
