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

Jane Ying Chieh Lee, Ching Wen Kuo, Shing Ling Tsai, Siao Muk Cheng, Shang Hung Chen, Hsiu Han Chan, Chun Hui Lin, Kun Yuan Lin, Chien Feng Li, Jagat R. Kanwar, Euphemia Y. Leung, Carlos Chun Ho Cheung, Wei Jan Huang, Yi Ching Wang, Chun Hei Antonio Cheung

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25 Citations (Scopus)

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.

Original languageEnglish
Article number81
JournalFrontiers in Pharmacology
Volume7
Issue numberMAR
DOIs
Publication statusPublished - Mar 31 2016

Keywords

  • Breast cancer
  • HDAC
  • SAHA
  • Survivin
  • XIAP

ASJC Scopus subject areas

  • Pharmacology (medical)
  • Pharmacology

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    Lee, J. Y. C., Kuo, C. W., Tsai, S. L., Cheng, S. M., Chen, S. H., Chan, H. H., Lin, C. H., Lin, K. Y., Li, C. F., Kanwar, J. R., Leung, E. Y., Cheung, C. C. H., Huang, W. J., Wang, Y. C., & Cheung, C. H. A. (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, 7(MAR), [81]. https://doi.org/10.3389/fphar.2016.00081