Xu Zhenye, Wang Xiaoyan, Yu Ping, Zhang Yong, Huang Liang, Mao Enqiang, Han Yi
Department of Emergency, Ruijin Hospital Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Scand J Gastroenterol. 2024 Apr;59(4):437-444. doi: 10.1080/00365521.2023.2301331. Epub 2024 Jan 23.
Histone modifications, especially the lysine acetylation, have drawn increasing attention in cancer research area. The aim of this research is to explore the molecular mechanisms underlying the regulation of lysine acetyltransferase 2 A (KAT2A) on colorectal cancer (CRC).
Clinical samples were collected from patients with CRC. The expression and correlation between KAT2A and ferroptosis suppressor SLC7A11 and glutathione peroxidase 4 (GPX4) were measured by qPCR and Pearson correlation analysis. NCP cells were transfected with KAT2A overexpression vectors or siRNAs. The proliferation of cells was measured by CCK-8 and colony formation assay. Cell migration and invasion was analyzed by Transwell. The accumulation of lipid peroxidation, ferrous iron, and malondialdehyde (MDA) were analyzed to determine cell ferroptosis. The expression of cell metastasis biomarkers was measured by western blotting assay. Interaction between KAT2A with GPX4 gene was measured by chromatin immunoprecipitation (ChIP).
The KAT2A, GPX4, and SLC7A11 expression was notably elevated in tumor tissues compared with the paired non-tumor tissues from CRC patients. The expression of KAT2A showed positive correlation with GPX4 and SLC7A11. Overexpression of KAT2A recovered the cell proliferation, migration, and invasion of CRC cells that suppressed by ferroptosis inducer erastin, along with deceased levels of ROS, iron, Fe2+, and MDA. Overexpression of KAT2A suppressed E-cadherin level and increased N-cadherin, Snail, and Vimentin expression in CRC cells. KAT2A interacted with GPX4 promoter region.
In conclusion, our findings demonstrated that KAT2A modulates the histone acetylation of GPX4 to regulate proliferation, metastasis, and ferroptosis of CRC cells.
组蛋白修饰，尤其是赖氨酸乙酰化，在癌症研究领域受到越来越多的关注。本研究旨在探讨赖氨酸乙酰转移酶2A（KAT2A）对结直肠癌（CRC）调控的分子机制。
收集CRC患者的临床样本。通过qPCR和Pearson相关性分析检测KAT2A与铁死亡抑制因子SLC7A11和谷胱甘肽过氧化物酶4（GPX4）之间的表达及相关性。用KAT2A过表达载体或小干扰RNA转染NCP细胞。通过CCK-8和集落形成试验检测细胞增殖。用Transwell分析细胞迁移和侵袭。分析脂质过氧化、亚铁离子和丙二醛（MDA）的积累以确定细胞铁死亡。通过蛋白质免疫印迹法检测细胞转移生物标志物的表达。用染色质免疫沉淀（ChIP）法检测KAT2A与GPX4基因之间的相互作用。
与CRC患者配对的非肿瘤组织相比，肿瘤组织中KAT2A、GPX4和SLC7A11的表达显著升高。KAT2A的表达与GPX4和SLC7A11呈正相关。KAT2A的过表达恢复了被铁死亡诱导剂erastin抑制的CRC细胞的增殖、迁移和侵袭能力，同时降低了活性氧、铁、亚铁离子和MDA的水平。KAT2A的过表达抑制了CRC细胞中E-钙黏蛋白的水平，并增加了N-钙黏蛋白、Snail和波形蛋白的表达。KAT2A与GPX4启动子区域相互作用。
总之，我们的研究结果表明，KAT2A通过调节GPX4的组蛋白乙酰化来调控CRC细胞的增殖、转移和铁死亡。
