Wang Wei, Chen Xiaoshan, Wei Wei
Department of Hepatobiliary and Pancreatic Surgery, Xiamen Humanity Hospital Fujian Medical University, Xiamen, PR China.
Department of Infectious Diseases, Zhongshan Hospital of Xiamen University, Xiamen, PR China.
Histol Histopathol. 2025 Aug;40(8):1295-1307. doi: 10.14670/HH-18-856. Epub 2024 Nov 29.
Hepatocellular carcinoma (HCC) is a highly fatal cancer. This study aims to investigate the underlying mechanism of tripartite motif-containing 22 (TRIM22) in HCC cell invasion and metastasis through the K (lysine) acetyltransferase 2A (KAT2A)/glutathione peroxidase 4 (GPX4) axis.
Human HCC cells BEL7405 were cultured and treated with MG-132, Ferrostain-1, pcDNA3.1-TRIM22, pcDNA3.1-KAT2A, or pcDNA3.1-NC. TRIM22-KAT2A interaction and KAT2A ubiquitination level, cell proliferation, invasion, migration, and histone H3 lysine 9 acetylation (H3K9ac) enrichment level on the GPX4 promoter were assessed by Co-IP, CCK-8, Transwell, and ChIP-qPCR assays. Mice were injected subcutaneously with Lv-oe-NC or Lv-oe-TRIM22 BEL7405 cells via the tail vein. Tumor proliferation and levels of TRIM22, KAT2A, GPX4, Fe, malondialdehyde (MDA), reactive oxygen species (ROS), and glutathione (GSH) in tissues and cells were evaluated by immunohistochemistry, RT-qPCR, western blot, and kits.
oe-TRIM22-treated BEL7405 cells exhibited increased TRIM22 expression, and abated KAT2A protein expression and malignant cell biological behaviors, which were partially reversed by upregulating KAT2A or suppressing ferroptosis. TRIM22 interacted with KAT2A, which was ubiquitinated to regulate GPX4 histone acetylation. TRIM22 overexpression elevated Fe, MDA, and ROS levels and cell death, and diminished GSH, GPX4, and H3K9ac enrichment levels, whereas further overexpression of KAT2A brought about opposite trends. TRIM22 suppressed HCC growth and metastasis by mediating ferroptosis through the KAT2A/GPX4 axis.
TRIM22 promoted KAT2A ubiquitination degradation to reduce H3K9ac enrichment levels in the GPX4 promoter region, and facilitated ferroptosis, thereby inhibiting HCC cell invasion and metastasis and growth and metastasis.
肝细胞癌（HCC）是一种致死率很高的癌症。本研究旨在通过赖氨酸乙酰转移酶2A（KAT2A）/谷胱甘肽过氧化物酶4（GPX4）轴，探讨含三联基序蛋白22（TRIM22）在肝癌细胞侵袭和转移中的潜在机制。
培养人肝癌细胞BEL7405，并用MG-132、铁死亡抑制剂1、pcDNA3.1-TRIM22、pcDNA3.1-KAT2A或pcDNA3.1-NC处理。通过免疫共沉淀（Co-IP）、细胞计数试剂盒-8（CCK-8）、Transwell和染色质免疫沉淀-定量聚合酶链反应（ChIP-qPCR）检测TRIM22与KAT2A的相互作用、KAT2A的泛素化水平、细胞增殖、侵袭、迁移以及GPX4启动子上组蛋白H3赖氨酸9乙酰化（H3K9ac）富集水平。通过尾静脉向小鼠皮下注射Lv-oe-NC或Lv-oe-TRIM22 BEL7405细胞。通过免疫组织化学、逆转录定量聚合酶链反应（RT-qPCR）、蛋白质免疫印迹法和试剂盒评估肿瘤增殖以及组织和细胞中TRIM22、KAT2A、GPX4、铁、丙二醛（MDA）、活性氧（ROS）和谷胱甘肽（GSH）的水平。
经oe-TRIM22处理的BEL7405细胞中TRIM22表达增加，KAT2A蛋白表达及恶性细胞生物学行为减弱，上调KAT2A或抑制铁死亡可部分逆转上述变化。TRIM22与KAT2A相互作用，KAT2A发生泛素化以调节GPX4组蛋白乙酰化。TRIM22过表达使铁、MDA和ROS水平升高以及细胞死亡增加，使GSH、GPX4和H3K9ac富集水平降低，而进一步过表达KAT2A则产生相反趋势。TRIM22通过KAT2A/GPX4轴介导铁死亡，从而抑制肝癌细胞的侵袭、转移、生长和扩散。
TRIM22促进KAT2A泛素化降解，以降低GPX4启动子区域的H3K9ac富集水平，并促进铁死亡，从而抑制肝癌细胞的侵袭、转移、生长和扩散。
