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Open AccessArticle

A New Histone Deacetylase Inhibitor Enhances Radiation Sensitivity through the Induction of Misfolded Protein Aggregation and Autophagy in Triple-Negative Breast Cancer

by Hui-Wen Chiu 1,2,†, Ya-Ling Yeh 3, Sheng-Yow Ho 4,5, Yuan-Hua Wu 3,6, Bour-Jr Wang 7,8, Wei-Jan Huang 9, Yuan-Soon Ho 10,11,12,13, Ying-Jan Wang 3, Li-Ching Chen 10,14,15,† and Shih-Hsin Tu 14,15,16,*
1
Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan
2
Division of Nephrology, Department of Internal Medicine, Shuang Ho Hospital, Taipei Medical University, Taipei 11031, Taiwan
3
Department of Environmental and Occupational Health, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan
4
Department of Radiation Oncology, Chi Mei Medical Center, Tainan 71004, Taiwan
5
Graduate Institute of Medical Sciences, Chang Jung Christian University, Tainan 71101, Taiwan
6
Department of Radiation Oncology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan
7
Department of Occupational and Environmental Medicine, National Cheng Kung University Hospital, Tainan 70101, Taiwan
8
Department of Cosmetic Science and Institute of Cosmetic Science, Chia Nan University of Pharmacy and Science, Tainan 71710, Taiwan
9
Graduate Institute of Pharmacognosy, Taipei Medical University, Taipei 11031, Taiwan
10
TMU Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei 11031, Taiwan
11
Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan
12
Department of Laboratory Medicine, Taipei Medical University Hospital, Taipei 11031, Taiwan
13
School of Medical Laboratory Science and Biotechnology, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan
14
Division of Breast Surgery, Department of Surgery, Taipei Medical University Hospital, Taipei 11031, Taiwan
15
Taipei Cancer Center, Taipei Medical University, Taipei 11031, Taiwan
16
Department of Surgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan
*
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Cancers 2019, 11(11), 1703; https://doi.org/10.3390/cancers11111703
Received: 18 September 2019 / Revised: 27 October 2019 / Accepted: 29 October 2019 / Published: 1 November 2019
Radiation therapy (RT) is one of the main treatments for triple-negative breast cancer (TNBC). However, many patients experience RT failure due to the metastatic potential of RT and the radiation resistance of several cancers. Histone deacetylase inhibitors (HDACis) can serve as radiosensitizers. In this study, we investigated whether a novel HDACi, TMU-35435, could reinforce radiosensitivity through the induction of misfolded protein aggregation and autophagy in TNBC. Significantly enhanced toxicity was found for the combination treatment compared with TMU-35435 or irradiation (IR) treatment alone in TNBC cells. The combination treatment induced misfolded protein aggregation and TMU-35435 inhibited the interaction of HDAC6 with dynein. Furthermore, the combined treatment induced endoplasmic reticulum (ER) stress but did not trigger apoptosis. In addition, the combination treatment caused autophagic cell death. Tumor growth in the mouse of model orthotopic breast cancer was suppressed by the combination treatment through the induction of ER stress and autophagy. These findings support the future evaluation of the novel HDACi TMU-35435, as a potent radiosensitizer in TNBC. View Full-Text
Keywords: histone deacetylase inhibitor; aggresome; radiation; autophagy; triple-negative breast cancer histone deacetylase inhibitor; aggresome; radiation; autophagy; triple-negative breast cancer
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Chiu, H.-W.; Yeh, Y.-L.; Ho, S.-Y.; Wu, Y.-H.; Wang, B.-J.; Huang, W.-J.; Ho, Y.-S.; Wang, Y.-J.; Chen, L.-C.; Tu, S.-H. A New Histone Deacetylase Inhibitor Enhances Radiation Sensitivity through the Induction of Misfolded Protein Aggregation and Autophagy in Triple-Negative Breast Cancer. Cancers 2019, 11, 1703.

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