2. Academic Validation
  3. HIV Tat- conjugated Histone H3 peptides induce tumor cell death via cellular stress responses

HIV Tat- conjugated Histone H3 peptides induce tumor cell death via cellular stress responses

  • Hum Gene Ther. 2022 Nov 14. doi: 10.1089/hum.2022.165.
Qian Xu 1,  Feimei Zhu 2,  Yixuan Pan 3,  Yanlin Ren 4,  Jingyu Li 5,  Ning Huang 6,  Keyun Liu 7,  Yi Wang 8
Affiliations

Affiliations

  • 1 Sichuan University West China School of Basic Medical Sciences and Forensic Medicine, 617323, Chengdu, Sichuan, China; xqqingmo@163.com.
  • 2 Sichuan University West China School of Basic Medical Sciences and Forensic Medicine, 617323, Chengdu, Sichuan, China; 250123999@qq.com.
  • 3 Shanghai Jiao Tong University School of Medicine, 56694, Shanghai, China; panyixuan@sjtu.edu.cn.
  • 4 Sichuan University West China School of Basic Medical Sciences and Forensic Medicine, 617323, Chengdu, Sichuan, China; 602147760@qq.com.
  • 5 Sichuan University West China School of Basic Medical Sciences and Forensic Medicine, 617323, Chengdu, Sichuan, China; 411514325@qq.com.
  • 6 Sichuan University West China School of Basic Medical Sciences and Forensic Medicine, 617323, Chengdu, Sichuan, China; huangpanxiao@sina.com.
  • 7 Hubei Minzu University, 271784, Enshi, Hubei , China; 33434246@qq.com.
  • 8 Sichuan University West China School of Basic Medical Sciences and Forensic Medicine, 617323, Chengdu, Sichuan, China; wy4504228@163.com.
PMID: 36373826 DOI: 10.1089/hum.2022.165
Abstract

Histone H3 is a nucleosome scaffold protein that is involved in a variety of intracellular processes. Aberrant modification of H3 is important in carcinogenesis. In contrast, free histones in cells can act as stimuli to trigger cellular immune responses and cell death. In this study, we linked cell-penetrating peptide HIV Tat to a histone H3 fragment to achieve intracellular delivery in tumor cells. We found that Tat-conjugated histone polypeptides localized to nuclei of lung and breast Cancer cells and caused cell death. A trans-configured Tat sequence displayed dramatically improved peptide half-life and cytotoxicity. Mechanistic studies demonstrated that treatment with the Peptides significantly elevated MAPK signaling, ROS production, as well as levels of stress-inducible transcription factor ATF3 and AP-1. Cytotoxicity of the peptide was significantly reduced by inhibition of AP-1 activity and ROS production. These results suggest the potential of Tat-conjugated H3 Peptides as antitumor agents to induce cell death via increased cellular stress response by activating p38-MAPK signaling and intracellular ROS production.

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