Li Yize, Zhao Yongmei, Peng Hongyan, Zhang Jing, Bo Lun, Wen Lei, Liu Wenchao, Bai Wendong, Zhang Hongmei
Department of Clinical Oncology, Xijing Hospital, Fourth Military Medical University, Xi'an, China.
Department of Hematology, Xinjiang Command General Hospital of Chinese People's Liberation Army, Urumqi, China.
Front Oncol. 2021 Sep 23;11:746266. doi: 10.3389/fonc.2021.746266. eCollection 2021.
Inhibitors of histone deacetylases (HDACi) have shown promising effects in preclinical applications for the treatment of many diseases. Confusedly though, the effects of the HDACi trichostatin A (TSA) on angiogenesis are variable among different diseases. This study investigated the direct effects of TSA on endothelial cells, which plays essential roles in angiogenesis and the underlying molecular events. TSA reduced the viability of human umbilical vein endothelial cells (HUVECs), in which proliferation-related genes including , , and were found to be involved. Furthermore, signal transducer and activator of transcription 5 A (STAT5A) was demonstrated to be reduced by TSA and to mediate TSA-induced downregulation of , , and and HUVEC proliferation. Mechanistically, data showed that STAT5A directly bound to the promoters of , , and and activated their transcription through special DNA sequence sites. Finally, the TSA-STAT5A-, , and axis also worked in a cancerous endothelial cell angiogenesis model. The results of this study revealed novel mechanisms underlying the effects of TSA on endothelial cells and provided insights for angiogenesis-associated diseases.
组蛋白去乙酰化酶抑制剂（HDACi）在多种疾病治疗的临床前应用中已显示出有前景的效果。然而，令人困惑的是，HDACi曲古抑菌素A（TSA）对血管生成的影响在不同疾病中存在差异。本研究调查了TSA对内皮细胞的直接作用，内皮细胞在血管生成及潜在分子事件中起关键作用。TSA降低了人脐静脉内皮细胞（HUVECs）的活力，发现包括 、 和 在内的与增殖相关的基因参与其中。此外，信号转导和转录激活因子5A（STAT5A）被证明会被TSA降低，并介导TSA诱导的 、 和 的下调以及HUVEC增殖。从机制上讲，数据表明STAT5A直接结合到 、 和 的启动子上，并通过特殊的DNA序列位点激活它们的转录。最后，TSA-STAT5A- 、 和 轴在癌性内皮细胞血管生成模型中也起作用。本研究结果揭示了TSA对内皮细胞作用的新机制，并为血管生成相关疾病提供了见解。
