Inhibition of HDAC3- and HDAC6-promoted survivin expression plays an important role in SAHA-induced autophagy and viability reduction in breast cancer cells

Lee, Jane Ying-Chieh, Kuo, Ching-Wen, Tsai, Shing-Ling, Cheng, Siao Muk, Chen, Shang-Hung, Chan, Hsiu-Han, Lin, Chun-Hui, Lin, Kun-Yuan, Li, Chien-Feng, Kanwar, Jagat R, Leung, Euphemia Y, Cheung, Carlos Chun Ho, Huang, Wei-Jan, Wang, Yi-Ching and Cheung, Chun Hei Antonio 2016, Inhibition of HDAC3- and HDAC6-promoted survivin expression plays an important role in SAHA-induced autophagy and viability reduction in breast cancer cells, Frontiers in pharmacology, vol. 7, pp. 1-13, doi: 10.3389/fphar.2016.00081.

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Title Inhibition of HDAC3- and HDAC6-promoted survivin expression plays an important role in SAHA-induced autophagy and viability reduction in breast cancer cells
Author(s) Lee, Jane Ying-Chieh
Kuo, Ching-Wen
Tsai, Shing-Ling
Cheng, Siao Muk
Chen, Shang-Hung
Chan, Hsiu-Han
Lin, Chun-Hui
Lin, Kun-Yuan
Li, Chien-Feng
Kanwar, Jagat RORCID iD for Kanwar, Jagat R orcid.org/0000-0003-3728-9568
Leung, Euphemia Y
Cheung, Carlos Chun Ho
Huang, Wei-Jan
Wang, Yi-Ching
Cheung, Chun Hei Antonio
Journal name Frontiers in pharmacology
Volume number 7
Start page 1
End page 13
Total pages 13
Publisher Frontiers Media
Place of publication Lausanne, Switzerland
Publication date 2016-03
ISSN 1663-9812
Keyword(s) HDAC
SAHA
XIAP
breast cancer
survivin
Science & Technology
Life Sciences & Biomedicine
Pharmacology & Pharmacy
HISTONE DEACETYLASE INHIBITOR
TRICHOSTATIN-A
APOPTOSIS
DEATH
ACTIVATION
ACETYLATION
DEPRIVATION
MECHANISM
PATHWAY
Summary 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.
Language eng
DOI 10.3389/fphar.2016.00081
Field of Research 111299 Oncology and Carcinogenesis not elsewhere classified
1115 Pharmacology And Pharmaceutical Sciences
Socio Economic Objective 920102 Cancer and Related Disorders
HERDC Research category C1 Refereed article in a scholarly journal
ERA Research output type C Journal article
Copyright notice ©2016, Lee et al.
Persistent URL http://hdl.handle.net/10536/DRO/DU:30085923

Document type: Journal Article
Collection: School of Medicine
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