Inhibition of HDAC3- and HDAC6-promoted survivin expression plays an important role in SAHA-induced autophagy and viability reduction in breast cancer cells
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 ce...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2016-03-01
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| Series: | Frontiers in Pharmacology |
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| Online Access: | http://journal.frontiersin.org/Journal/10.3389/fphar.2016.00081/full |
| _version_ | 1818841552198303744 |
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| author | Jane Ying-Chieh Lee Ching-Wen eKuo Shing-Ling eTsai Siao Muk eCheng Shang-Hung eChen Hsiu-Han eChan Chun-Hui eLin Kun-Yuan eLin Chien-Feng eLi Jagat Rakesh Kanwar Euphemia Yee Leung Carlos Chun Ho Cheung Wei-Jan eHuang Yi-Ching eWang Chun Hei Antonio eCheung |
| author_facet | Jane Ying-Chieh Lee Ching-Wen eKuo Shing-Ling eTsai Siao Muk eCheng Shang-Hung eChen Hsiu-Han eChan Chun-Hui eLin Kun-Yuan eLin Chien-Feng eLi Jagat Rakesh Kanwar Euphemia Yee Leung Carlos Chun Ho Cheung Wei-Jan eHuang Yi-Ching eWang Chun Hei Antonio eCheung |
| author_sort | Jane Ying-Chieh Lee |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-19T04:27:53Z |
| format | Article |
| id | doaj.art-3859361799114d13b9529b2149fa899a |
| institution | Directory Open Access Journal |
| issn | 1663-9812 |
| language | English |
| last_indexed | 2024-12-19T04:27:53Z |
| publishDate | 2016-03-01 |
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| series | Frontiers in Pharmacology |
| spelling | doaj.art-3859361799114d13b9529b2149fa899a2022-12-21T20:35:57ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122016-03-01710.3389/fphar.2016.00081186606Inhibition of HDAC3- and HDAC6-promoted survivin expression plays an important role in SAHA-induced autophagy and viability reduction in breast cancer cellsJane Ying-Chieh Lee0Ching-Wen eKuo1Shing-Ling eTsai2Siao Muk eCheng3Shang-Hung eChen4Hsiu-Han eChan5Chun-Hui eLin6Kun-Yuan eLin7Chien-Feng eLi8Jagat Rakesh Kanwar9Euphemia Yee Leung10Carlos Chun Ho Cheung11Wei-Jan eHuang12Yi-Ching eWang13Chun Hei Antonio eCheung14National Cheng Kung UniversityNational Cheng Kung UniversityNational Cheng Kung UniversityNational Cheng Kung UniversityChi-Mei Medical CenterNational Cheng Kung UniversityNational Cheng Kung UniversityNational Cheng Kung UniversityChi-Mei Medical CenterDeakinUniversity of AucklandUniversity of AucklandTaipei Medical UniversityNational Cheng Kung UniversityNational Cheng Kung UniversitySAHA 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.http://journal.frontiersin.org/Journal/10.3389/fphar.2016.00081/fullbreast cancerHDACXIAPsurvivinSAHA |
| spellingShingle | Jane Ying-Chieh Lee Ching-Wen eKuo Shing-Ling eTsai Siao Muk eCheng Shang-Hung eChen Hsiu-Han eChan Chun-Hui eLin Kun-Yuan eLin Chien-Feng eLi Jagat Rakesh Kanwar Euphemia Yee Leung Carlos Chun Ho Cheung Wei-Jan eHuang Yi-Ching eWang Chun Hei Antonio eCheung 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 breast cancer HDAC XIAP survivin SAHA |
| title | Inhibition of HDAC3- and HDAC6-promoted survivin expression plays an important role in SAHA-induced autophagy and viability reduction in breast cancer cells |
| title_full | Inhibition of HDAC3- and HDAC6-promoted survivin expression plays an important role in SAHA-induced autophagy and viability reduction in breast cancer cells |
| title_fullStr | Inhibition of HDAC3- and HDAC6-promoted survivin expression plays an important role in SAHA-induced autophagy and viability reduction in breast cancer cells |
| title_full_unstemmed | Inhibition of HDAC3- and HDAC6-promoted survivin expression plays an important role in SAHA-induced autophagy and viability reduction in breast cancer cells |
| title_short | Inhibition of HDAC3- and HDAC6-promoted survivin expression plays an important role in SAHA-induced autophagy and viability reduction in breast cancer cells |
| title_sort | inhibition of hdac3 and hdac6 promoted survivin expression plays an important role in saha induced autophagy and viability reduction in breast cancer cells |
| topic | breast cancer HDAC XIAP survivin SAHA |
| url | http://journal.frontiersin.org/Journal/10.3389/fphar.2016.00081/full |
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