1. Academic Validation
  2. The HDAC inhibitor HFY-4A improves TUSC2 transcription to induce immunogenic cell death in breast cancer

The HDAC inhibitor HFY-4A improves TUSC2 transcription to induce immunogenic cell death in breast cancer

  • Toxicol Appl Pharmacol. 2023 Sep 22;116698. doi: 10.1016/j.taap.2023.116698.
Yongshuo Yin 1 Xiao Guan 2 Genju Li 3 Chen Chen 4 Yangmiao Duan 5 Zhiyong Yu 6
Affiliations

Affiliations

  • 1 Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, PR China; Department of Breast Surgery, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong 250117, PR China.
  • 2 Department of Health Management Center, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250063, PR China.
  • 3 School of Pharmaceutical Sciences, Shandong University, Jinan, Shandong 250100, PR China.
  • 4 School of Pharmaceutical Sciences, Qilu University of Technology, Jinan, Shandong 250353, PR China.
  • 5 School of Basic Medical Sciences, Shandong University, Jinan, Shandong 250100, PR China.
  • 6 Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, PR China; Department of Breast Surgery, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong 250117, PR China. Electronic address: zyyu@sdfmu.edu.cn.
Abstract

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.

Keywords

Breast cancer; HDAC; HFY-4A; ICD; TUSC2 transcription.

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