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Open AccessArticle

Induction of Apoptosis and Autophagy in Breast Cancer Cells by a Novel HDAC8 Inhibitor

by Chang-Fang Chiu 1,2,3,†, Hsien-Kuo Chin 4,5,†, Wei-Jan Huang 6,†, Li-Yuan Bai 1,3, Hao-Yu Huang 5 and Jing-Ru Weng 5,6,7,8,*
1
Division of Hematology and Oncology, Department of Internal Medicine, China Medical University Hospital, Taichung 40447, Taiwan
2
Cancer Center, China Medical University Hospital, Taichung 40415, Taiwan
3
College of Medicine, China Medical University, Taichung 40402, Taiwan
4
Division of Cardiovascular Surgery, Department of Surgery, Kaohsiung Armed Forces General Hospital, Kaohsiung 80284, Taiwan
5
Department of Marine Biotechnology and Resources, National Sun Yat-sen University, Kaohsiung 80424, Taiwan
6
Graduate Institute of Pharmacognosy, College of Pharmacy, Taipei Medical University, Taipei 11031, Taiwan
7
Doctoral Degree Program in Marine Biotechnology, National Sun Yat-sen University, Kaohsiung 80424, Taiwan
8
Graduate Institute of Natural Products, College of Pharmacy, Kaohsiung Medical University, Kaohsiung 80715, Taiwan
*
Author to whom correspondence should be addressed.
These authors contributed equally to this paper.
Biomolecules 2019, 9(12), 824; https://doi.org/10.3390/biom9120824
Received: 29 October 2019 / Revised: 30 November 2019 / Accepted: 30 November 2019 / Published: 4 December 2019
: Epigenetic therapy has been demonstrated to be a viable strategy for breast cancer treatment. In this study, we report the anti-tumor activity of a hydroxamate-based histone deacetylase (HDAC)8-selective inhibitor, HMC, in breast cancer cells. MTT assays showed that HMC inhibited cell viability of MCF-7 and MDA-MB-231 cells with IC50 values of 7.7 μM and 9.5 μM, respectively. HMC induced caspase-dependent apoptosis in MCF-7 cells, which was associated with its ability to modulate a series of cell survival-related signaling effectors, including Akt, mTOR, Bax, Mcl-1, and Bcl-2. Additionally, HMC was capable of activating PPARγ, which was accompanied by reduced expression of PPARγ target gene products, such as cyclin D1 and CDK6. HMC increased the production of ROS in MCF-7 cells, which could be partially reversed by the cotreatment with a ROS scavenger (N-acetylcysteine or glutathione). Furthermore, HMC induced autophagy, as characterized by the formation of acidic vesicular organelles and autophagic biomarkers including LC3B-II and Atg5. Notably, pharmacological blockade of autophagy by 3-MA or CQ could attenuate HMC-induced apoptosis, suggesting that autophagy played a self-protective role in HMC-induced cell death. Together, these data suggest the translational potential of HMC to be developed into a potential therapeutic agent for breast cancer therapy.
Keywords: histone deacetylase; HDAC8-selective inhibitor; breast cancer; apoptosis; autophagy; PPARγ; ROS histone deacetylase; HDAC8-selective inhibitor; breast cancer; apoptosis; autophagy; PPARγ; ROS
MDPI and ACS Style

Chiu, C.-F.; Chin, H.-K.; Huang, W.-J.; Bai, L.-Y.; Huang, H.-Y.; Weng, J.-R. Induction of Apoptosis and Autophagy in Breast Cancer Cells by a Novel HDAC8 Inhibitor. Biomolecules 2019, 9, 824.

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