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Article: SIRT6 modulates paclitaxel and epirubicin resistance and survival in breast cancer

TitleSIRT6 modulates paclitaxel and epirubicin resistance and survival in breast cancer
Authors
Issue Date2013
PublisherOxford University Press. The Journal's web site is located at http://carcin.oxfordjournals.org/
Citation
Carcinogenesis, 2013, v. 34 n. 7, p. 1476-1486 How to Cite?
AbstractIn this study, we report the identification of a novel role of SIRT6 in both epirubicin and paclitaxel resistance in breast cancer. We found that SIRT6 protein levels are elevated in paclitaxel- and epirubicin-resistant MCF-7 cells compared with the parental sensitive cells. SIRT6 knockout and depletion sensitized cells to both paclitaxel and epirubicin treatment, whereas SIRT6 ectopic overexpression led to increased resistance to paclitaxel and epirubicin. Moreover, our data suggest that SIRT6 could be mediating epirubicin resistance through enhancing the DNA repair response to epirubicin-induced DNA damage. Clonogenic assays also revealed that mouse embryonic fibroblasts (MEFs) lacking SIRT6 have decreased long-term viability in response to epirubicin. The tumour suppressor FOXO3a increases its levels of acetylation in MEFs depleted of SIRT6, whereas its induction by epirubicin is attenuated in breast cancer cells overexpressing SIRT6. Further cell viability studies demonstrate that deletion of FOXO1/3/4 in MEFs can confer sensitivity to both paclitaxel and epirubicin, suggesting that SIRT6 reduces paclitaxel and epirubicin sensitivity, at least in part, through modulating FOXO acetylation and expression. Consistently, immunohistochemical analysis of 118 breast cancer patient samples revealed that high SIRT6 nuclear staining is significantly associated with poorer overall survival (P = 0.018; Kaplan-Meier analysis). Multivariate Cox analysis demonstrated that nuclear SIRT6 staining remained associated with death after correcting for tumour stage and lymph-node involvement (P = 0.033). Collectively, our data suggest that SIRT6 has a role in paclitaxel and epirubicin sensitivity via targeting FOXO proteins and that SIRT6 could be a useful biomarker and therapeutic target for paclitaxel- and epirubicin-resistant cancer.
Persistent Identifierhttp://hdl.handle.net/10722/185793
ISSN
2015 Impact Factor: 4.874
2015 SCImago Journal Rankings: 2.439
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorKhongkow, M-
dc.contributor.authorOlmos, Y-
dc.contributor.authorGong, C-
dc.contributor.authorGomes, AR-
dc.contributor.authorMonteiro, LJ-
dc.contributor.authorYague, E-
dc.contributor.authorCavaco, TB-
dc.contributor.authorKhongkow, P-
dc.contributor.authorMan, EP-
dc.contributor.authorLaohasinnarong, S-
dc.contributor.authorKoo, CY-
dc.contributor.authorHarada-Shoji, N-
dc.contributor.authorTsang, JWH-
dc.contributor.authorCoombes, RC-
dc.contributor.authorSchwer, B-
dc.contributor.authorKhoo, US-
dc.contributor.authorLam, EW-
dc.date.accessioned2013-08-20T11:41:19Z-
dc.date.available2013-08-20T11:41:19Z-
dc.date.issued2013-
dc.identifier.citationCarcinogenesis, 2013, v. 34 n. 7, p. 1476-1486-
dc.identifier.issn0143-3334-
dc.identifier.urihttp://hdl.handle.net/10722/185793-
dc.description.abstractIn this study, we report the identification of a novel role of SIRT6 in both epirubicin and paclitaxel resistance in breast cancer. We found that SIRT6 protein levels are elevated in paclitaxel- and epirubicin-resistant MCF-7 cells compared with the parental sensitive cells. SIRT6 knockout and depletion sensitized cells to both paclitaxel and epirubicin treatment, whereas SIRT6 ectopic overexpression led to increased resistance to paclitaxel and epirubicin. Moreover, our data suggest that SIRT6 could be mediating epirubicin resistance through enhancing the DNA repair response to epirubicin-induced DNA damage. Clonogenic assays also revealed that mouse embryonic fibroblasts (MEFs) lacking SIRT6 have decreased long-term viability in response to epirubicin. The tumour suppressor FOXO3a increases its levels of acetylation in MEFs depleted of SIRT6, whereas its induction by epirubicin is attenuated in breast cancer cells overexpressing SIRT6. Further cell viability studies demonstrate that deletion of FOXO1/3/4 in MEFs can confer sensitivity to both paclitaxel and epirubicin, suggesting that SIRT6 reduces paclitaxel and epirubicin sensitivity, at least in part, through modulating FOXO acetylation and expression. Consistently, immunohistochemical analysis of 118 breast cancer patient samples revealed that high SIRT6 nuclear staining is significantly associated with poorer overall survival (P = 0.018; Kaplan-Meier analysis). Multivariate Cox analysis demonstrated that nuclear SIRT6 staining remained associated with death after correcting for tumour stage and lymph-node involvement (P = 0.033). Collectively, our data suggest that SIRT6 has a role in paclitaxel and epirubicin sensitivity via targeting FOXO proteins and that SIRT6 could be a useful biomarker and therapeutic target for paclitaxel- and epirubicin-resistant cancer.-
dc.languageeng-
dc.publisherOxford University Press. The Journal's web site is located at http://carcin.oxfordjournals.org/-
dc.relation.ispartofCarcinogenesis-
dc.rightsPre-print: Journal Title] ©: [year] [owner as specified on the article] Published by Oxford University Press [on behalf of xxxxxx]. All rights reserved. Pre-print (Once an article is published, preprint notice should be amended to): This is an electronic version of an article published in [include the complete citation information for the final version of the Article as published in the print edition of the Journal.] Post-print: This is a pre-copy-editing, author-produced PDF of an article accepted for publication in [insert journal title] following peer review. The definitive publisher-authenticated version [insert complete citation information here] is available online at: xxxxxxx [insert URL that the author will receive upon publication here].-
dc.titleSIRT6 modulates paclitaxel and epirubicin resistance and survival in breast cancer-
dc.typeArticle-
dc.identifier.emailTsang, JWH: jwhtsang@hku.hk-
dc.identifier.emailKhoo, US: uskhoo@hku.hk-
dc.identifier.authorityTsang, JWH=rp00278-
dc.identifier.authorityKhoo, US=rp00362-
dc.identifier.doi10.1093/carcin/bgt098-
dc.identifier.pmid23514751-
dc.identifier.hkuros220094-
dc.identifier.hkuros226503-
dc.identifier.volume34-
dc.identifier.issue7-
dc.identifier.spage1476-
dc.identifier.epage1486-
dc.identifier.isiWOS:000321753000008-
dc.publisher.placeUnited Kingdom-

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