title: Inhibition of HDAC3- and HDAC6-Promoted Survivin Expression Plays an Important Role in SAHA-Induced Autophagy and Viability Reduction in Breast Cancer Cells.
abstract: SAHA is a class I HDAC/HDAC6 co-inhibitor and an autophagy inducer currently undergoing clinical investigations in breast cancer patients. However, the molecular mechanism of action of SAHA in breast cancer cells remains unclear. In this study, we found that SAHA is equally effective in targeting cells of different breast cancer subtypes and tamoxifen sensitivity. Importantly, we found that down-regulation of survivin plays an important role in SAHA-induced autophagy and cell viability reduction in human breast cancer cells. SAHA decreased survivin and XIAP gene transcription, induced survivin protein acetylation and early nuclear translocation in MCF7 and MDA-MB-231 breast cancer cells. It also reduced survivin and XIAP protein stability in part through modulating the expression and activation of the 26S proteasome and heat-shock protein 90. Interestingly, targeting HDAC3 and HDAC6, but not other HDAC isoforms, by siRNA/pharmacological inhibitors mimicked the effects of SAHA in modulating the acetylation, expression, and nuclear translocation of survivin and induced autophagy in MCF7 and MDA-MB-231 cancer cells. Targeting HDAC3 also mimicked the effect of SAHA in up-regulating the expression and activity of proteasome, which might lead to the reduced protein stability of survivin in breast cancer cells. In conclusion, this study provides new insights into SAHA's molecular mechanism of actions in breast cancer cells. Our findings emphasize the complexity of the regulatory roles in different HDAC isoforms and potentially assist in predicting the mechanism of novel HDAC inhibitors in targeted or combinational therapies in the future.
authors.affiliation: Department of Pharmacology, College of Medicine, National Cheng Kung University Tainan, Taiwan.
authors.forename: Jane Ying-Chieh
authors.initials: JY
authors.lastname: Lee
authors.affiliation: Department of Pharmacology, College of Medicine, National Cheng Kung University Tainan, Taiwan.
authors.forename: Ching-Wen
authors.initials: CW
authors.lastname: Kuo
authors.affiliation: Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University Tainan, Taiwan.
authors.forename: Shing-Ling
authors.initials: SL
authors.lastname: Tsai
authors.affiliation: Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University Tainan, Taiwan.
authors.forename: Siao Muk
authors.initials: SM
authors.lastname: Cheng
authors.affiliation: Division of Hematology and Oncology, Department of Internal Medicine, Chi-Mei Medical Center Liouying, Tainan, Taiwan.
authors.forename: Shang-Hung
authors.initials: SH
authors.lastname: Chen
authors.affiliation: Department of Pharmacology, College of Medicine, National Cheng Kung University Tainan, Taiwan.
authors.forename: Hsiu-Han
authors.initials: HH
authors.lastname: Chan
authors.affiliation: Department of Pharmacology, College of Medicine, National Cheng Kung University Tainan, Taiwan.
authors.forename: Chun-Hui
authors.initials: CH
authors.lastname: Lin
authors.affiliation: Department of Pharmacology, College of Medicine, National Cheng Kung University Tainan, Taiwan.
authors.forename: Kun-Yuan
authors.initials: KY
authors.lastname: Lin
authors.affiliation: Department of Pathology, Chi-Mei Medical Center, Yung Kang District Tainan, Taiwan.
authors.forename: Chien-Feng
authors.initials: CF
authors.lastname: Li
authors.affiliation: Nanomedicine-Laboratory of Immunology and Molecular Biology, Faculty of Health, School of Medicine, Deakin University Waurn Ponds, Geelong, VIC, Australia.
authors.forename: Jagat R
authors.initials: JR
authors.lastname: Kanwar
authors.affiliation: Auckland Cancer Society Research Centre and Department of Molecular Medicine and Pathology, University of Auckland Auckland, New Zealand.
authors.forename: Euphemia Y
authors.initials: EY
authors.lastname: Leung
authors.affiliation: School of Biological Sciences, Faculty of Science, University of Auckland Auckland, New Zealand.
authors.forename: Carlos Chun Ho
authors.initials: CC
authors.lastname: Cheung
authors.affiliation: Graduate Institute of Pharmacognosy, Taipei Medical University Taipei, Taiwan.
authors.forename: Wei-Jan
authors.initials: WJ
authors.lastname: Huang
authors.affiliation: Department of Pharmacology, College of Medicine, National Cheng Kung UniversityTainan, Taiwan; Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung UniversityTainan, Taiwan.
authors.forename: Yi-Ching
authors.initials: YC
authors.lastname: Wang
authors.affiliation: Department of Pharmacology, College of Medicine, National Cheng Kung UniversityTainan, Taiwan; Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung UniversityTainan, Taiwan.
authors.forename: Chun Hei Antonio
authors.initials: CH
authors.lastname: Cheung
keywords: HDAC; SAHA; XIAP; breast cancer; survivin