Yin Yongshuo, Guan Xiao, Li Genju, Chen Chen, Duan Yangmiao, Yu Zhiyong
Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, PR China; Department of Breast Surgery, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong 250117, PR China.
Department of Health Management Center, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250063, PR China.
Toxicol Appl Pharmacol. 2023 Nov 1;478:116698. doi: 10.1016/j.taap.2023.116698. Epub 2023 Sep 22.
We managed to explore the function of HFY-4A, a novel histone deacetylases (HDACs) inhibitor, on breast cancer as well as its potential mechanisms. MCF7 and T47D cells were treated with 0.8, 1.6 or 3.2 μM HFY-4A for 0-72 h, following of which CCK-8, colony formation, EdU staining, flow cytometry, Transwell, and wound healing assays were carried out. Western blot, immunohistochemistry, and ELISA were conducted for assaying the expression of immunogenic cell death (ICD)-related proteins. The interaction between HFY-4A, HDAC1, and tumor suppressor candidate 2 (TUSC2) was evaluated by chromatin immunoprecipitation assay. Further, the function of HFY-4A in breast cancer progression in vivo was evaluated using xenograft mouse models. HFY-4A inhibited the proliferation, migration, and invasion, and induced apoptosis of breast cancer cells in a dose-dependent manner. HFY-4A dose-dependently caused the ICD of breast cancer cells, as evidenced by the significant high levels of high-mobility group box 1 (HMGB1), calreticulin (CRT), heat shock protein 70 (HSP70), and HSP90. Interestingly, HFY-4A could facilitate TUSC2 transcription by promoting acetylation of histones on the TUSC2 promoter. The results of rescue assays revealed that HFY-4A repressed proliferation and mobility, but enhanced apoptosis and ICD through facilitating TUSC2 transcription in breast cancer. In breast cancer xenograft mouse models, HFY-4A was verified to inhibit tumor growth via upregulating TUSC2. HFY-4A could inhibit breast cancer cell proliferation and mobility, and enhanced apoptosis and ICD through facilitating TUSC2 transcription.
我们成功探究了新型组蛋白去乙酰化酶（HDACs）抑制剂HFY-4A对乳腺癌的作用及其潜在机制。用0.8、1.6或3.2 μM HFY-4A处理MCF7和T47D细胞0至72小时，之后进行CCK-8、集落形成、EdU染色、流式细胞术、Transwell和伤口愈合试验。通过蛋白质免疫印迹、免疫组织化学和酶联免疫吸附测定法检测免疫原性细胞死亡（ICD）相关蛋白的表达。采用染色质免疫沉淀试验评估HFY-4A、HDAC1和肿瘤抑制候选基因2（TUSC2）之间的相互作用。此外，利用异种移植小鼠模型评估HFY-4A在体内对乳腺癌进展的作用。HFY-4A以剂量依赖的方式抑制乳腺癌细胞的增殖、迁移和侵袭，并诱导其凋亡。HFY-4A以剂量依赖的方式引起乳腺癌细胞的ICD，高迁移率族蛋白B1（HMGB1）、钙网蛋白（CRT）、热休克蛋白70（HSP70）和HSP90的显著高水平证明了这一点。有趣的是，HFY-4A可通过促进TUSC2启动子上组蛋白的乙酰化来促进TUSC2转录。挽救试验结果显示，HFY-4A通过促进乳腺癌中的TUSC2转录来抑制增殖和迁移，但增强凋亡和ICD。在乳腺癌异种移植小鼠模型中，HFY-4A经证实可通过上调TUSC2来抑制肿瘤生长。HFY-4A可抑制乳腺癌细胞的增殖和迁移，并通过促进TUSC2转录增强凋亡和ICD。
