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Title: The role of SIRT6 and FOXO3a acetylation in the development of drug resistance in breast cancer
Author: Khongkow, Mattaka
ISNI:       0000 0004 6346 8081
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2015
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Drug resistance is one of most challenging problems that need to be addressed in order to improve treatment efficiency and overcome cancer. Apart from epigenetic changes, the regulation of transcription factors, such as p53 and E2F1, via deacetylation, independent of histone modification, have been documented to be involved in cancer progression and drug resistance. In this work, I demonstrated that sirtuins (deacetylase enzyme family) especially SIRT6, have a crucial role in the development of epirubicin and paclitaxel resistance in breast cancer. The levels of SIRT6 protein were elevated in MCF-7-epirubicin resistant- (MCF-7-EpiR) and -paclitaxel resistant cells (MCF-7-TaxR) compared to MCF-7 sensitive cells. The depletion of SIRT6 in both resistant cells sensitises these cells to epirubicin and paclitaxel treatments, whereas ectopic overexpression of SIRT6 in MCF-7 cells is sufficient to confer the resistance. I also found that the overexpression of SIRT6 prevents epirubicin induced cell death and cellular senescence by enhancing DNA damage repair. Moreover, its overexpression also deregulates G2/M cell cycle checkpoint induced by paclitaxel. FOXO3a and p53 are two main mediators for chemotherapeutic response and have been reported to be cellular targets of SIRT1 and SIRT2 via their deacetylase activities. Interestingly, the acetylation levels of these proteins are also regulated by SIRT6, as the levels of their acetylation are higher in Sirt6-/- MEFs compared to wild-type (WT) MEFs, especially in response to chemotherapy treatment. Additionally, the acetylation levels of FOXO3a are increased after SIRT6 depletion in MCF-7 cells. The depletion of SIRT1, -2, and -6 in MCF-7 as well as MCF-7-EpiR and MCF-7-TaxR cells increases the acetylation levels of FOXO3a compared to control cells. However, the acetylation levels of FOXO3a are noticeably higher in SIRT6 depleted cells compared to SIRT1 and SIRT2 depleted cells. These findings implicate SIRT6 as the main player in the regulation of FOXO3a acetylation in MCF-7 cells and SIRT6 reduces paclitaxel and epirubicin sensitivity, at least in part, through the modulation of FOXO3a acetylation and expression. Consistently, immunohistochemical analysis of breast cancer patient samples revealed that higher SIRT6 nuclear expression is significantly associated with poorer overall survival. Collectively, my study suggests that SIRT6 has a role in paclitaxel and epirubicin sensitivity via targeting the FOXO3a protein, and that SIRT6 could be a useful predictive biomarker and therapeutic target for paclitaxel and epirubicin resistant cancer.
Supervisor: Lam, Eric ; Tate, Ed Sponsor: Government of Thailand
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral