• J. Dermatol. Sci. · Sep 2018

    DNAJA4 deficiency enhances NF-kappa B-related growth arrest induced by hyperthermia in human keratinocytes.

    • Yu-Zhe Sun, Yi Ren, Yu-Jing Zhang, Yang Han, Yang Yang, Ya-Li Gao, Li-Li Zhu, Rui-Qun Qi, Hong-Duo Chen, and Xing-Hua Gao.
    • China Medical University, Shenyang, 110001, China; Department of Dermatology, No.1 Hospital of China Medical University, China; Key Laboratory of Immunodermatology, Ministry of Health and Ministry of Education, Shenyang, 110001, China.
    • J. Dermatol. Sci. 2018 Sep 1; 91 (3): 256-267.

    BackgroundHyperthermia is an effective treatment against cancer and human papillomavirus (HPV) infection. Previous studies have shown that heat shock proteins are crucial to the action of hyperthermia.ObjectivesTo examine the effects of hyperthermia in combination with DNAJA4-deficiency on human keratinocytes and Condyloma acumunatum (CA) tissues.MethodsHaCaT cells were subjected to 44°C (compared to 37°C) waterbath for 30min for stimulation. Foreskin or CA tissues obtained from patients undergoing circumcision or pathological examination were bisected and subjected to similar treatments. DNAJA4-knockout (KO) HaCaT cells were generated with CRISPR/Cas9 technology. mRNA and protein expressions were determined using rt-qPCR and western-blotting. Cell cycle distribution, apoptosis and senescence were analyzed by flow cytometry.ResultsDNAJA4 was induced in HaCaT cells, foreskin and CA tissues subjected to hyperthermia at both transcriptional and translational levels. NF-kB,3 was activated by hyperthermia in HaCaT cells, and further enhanced by DNAJA4-deficiency. Transcription of TNF-α4; IL-1B,5 TNFAIP36 and IL-87 were induced in HaCaT cells subjected to hyperthermia. DNAJA4-knockout promoted transcriptions of TNF-α and IL-1B, whereas decreased that of TNFAIP3 and IL-8. Reduced cell survival, proliferation and viability were demonstrated using flow cytometry and MTS assays. Furthermore, NF-kB inhibitors reversed most of the phenotypes observed.ConclusionsHyperthermia reduced HaCaT cell proliferation and promoted cytokine expressions responsible for anti-viral activity, mainly through a NF-kB dependent pathway. DNAJA4-deficiency enhanced the activation of NF-kB by hyperthermia in HaCaT cells, indicating that DNAJA4 may be a promising therapeutic target for use in the treatment of cutaneous HPV infections.Copyright © 2018 Japanese Society for Investigative Dermatology. Published by Elsevier B.V. All rights reserved.

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