title: SIRT6 modulates paclitaxel and epirubicin resistance and survival in breast cancer.
abstract: In 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.
authors.affiliation: Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital Campus, London W12 0NN, UK.
authors.forename: Mattaka
authors.initials: M
authors.lastname: Khongkow
authors.forename: Yolanda
authors.initials: Y
authors.lastname: Olmos
authors.forename: Chun
authors.initials: C
authors.lastname: Gong
authors.forename: Ana R
authors.initials: AR
authors.lastname: Gomes
authors.forename: Lara J
authors.initials: LJ
authors.lastname: Monteiro
authors.forename: Ernesto
authors.initials: E
authors.lastname: Yagüe
authors.forename: Tania B
authors.initials: TB
authors.lastname: Cavaco
authors.forename: Pasarat
authors.initials: P
authors.lastname: Khongkow
authors.forename: Ellen P S
authors.initials: EP
authors.lastname: Man
authors.forename: Sasiwan
authors.initials: S
authors.lastname: Laohasinnarong
authors.forename: Chuay-Yeng
authors.initials: CY
authors.lastname: Koo
authors.forename: Narumi
authors.initials: N
authors.lastname: Harada-Shoji
authors.forename: Janice W-H
authors.initials: JW
authors.lastname: Tsang
authors.forename: R Charles
authors.initials: RC
authors.lastname: Coombes
authors.forename: Bjoern
authors.initials: B
authors.lastname: Schwer
authors.forename: Ui-Soon
authors.initials: US
authors.lastname: Khoo
authors.forename: Eric W-F
authors.initials: EW
authors.lastname: Lam
mesh_terms: D000107:Acetylation; D000818:Animals; D014408:Biomarkers, Tumor / Q000378:metabolism; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology*; D016923:Cell Death; D002467:Cell Nucleus / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D004249:DNA Damage; D004260:DNA Repair; D019008:Drug Resistance, Neoplasm; D015251:Epirubicin / Q000494:pharmacology*; D005260:Female; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D055786:Gene Knockout Techniques; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D061986:MCF-7 Cells; D051379:Mice; D017239:Paclitaxel / Q000494:pharmacology*; D016016:Proportional Hazards Models; D037761:Sirtuins / Q000235:genetics / Q000378:metabolism*
chemical_list: D014408:Biomarkers, Tumor; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; C474033:FoxO3 protein, mouse; D015251:Epirubicin; C516592:SIRT6 protein, human; D037761:Sirtuins; D017239:Paclitaxel