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.

FOXO3a and Posttranslational Modifications Mediate Glucocorticoid Sensitivity in B-ALL

“…For example, it has been demonstrated that SIRT1 can antagonize the p300-mediated acetylation and activation of FOXO3a (21). In agreement, studies conducted in breast cancer have also showed that SIRT6 overexpression correlates with FOXO3a inactivation and that SIRT6 depletion sensitizes breast cancer cells to both paclitaxel and epirubicin treatments (22).…”

“…FOXO3a nuclear localization is associated with phosphorylation on Ser-7 and acetylation on Lys-242/245 in B-ALL cells Acetylation has been described to modulate the transcriptional activity of FOXO3a (22,40). In addition, a recent study has also demonstrated that JNK phosphorylation can promote FOXO1 acetylation and activation (41).…”

“…Specifically, p300/CBP has been shown to mediate the FOXO3a acetylation on Lys-242, Lys-245, and Lys-262 residues, whereas SIRT1, 2, and 6 have been shown to target FOXO3a for deacetylation (22,(42)(43)(44)(45). Western blot analysis showed that dexamethasone treatment upregulated CBP/p300 and downregulated SIRT1, 2, and 6 expression in the drug-sensitive RS4;11 and SUP-B15 cells (Fig.…”

Post-translational modifications of FOXO family proteins

“…Mammals have seven sirtuins, with sirtuin (SIRT) 1-3 exhibiting strong NAD + -dependent deacetylation activity, whereas SIRT4-7 exhibit strong deacetylation and are more accurately described as NAD + -dependent deacylases (77). SIRT2 is predominantly localized in the cytoplasm, whereas SIRT3, SIRT4 and SIRT5 are predominantly in the mitochondria, and SIRT1, SIRT6, SIRT7 in the nucleus (78). FOXO proteins are deacetylated by HDACs and sirtuins simultaneously.…”

“…In mouse embryonic fibroblasts, SIRT6 inhibition can increase the acetylation level of FOXO3a. However in breast cancer cells, overexpression of SIRT6, which reduces the acetylation level of FOXO3a, weakens the transcription activity of FOXO3a and generates resistance to epirubicin and paclitaxel, which suggests that inhibition of SIRT6 to upregulate the activity of FOXO3a may be a promising therapeutic strategy for breast cancer (78).…”