Mdm2-Mediated Degradation Of Sirt6 Phosphorylated By Akt1 Promotes Tumorigenesis And Trastuzumab Resistance In Breast Cancer

Author

Umadevi Thirumurthi, The University of Texas Graduate School of Biomedical Sciences at HoustonFollow

Date of Graduation

12-2014

Document Type

Dissertation (PhD)

Program Affiliation

Cancer Biology

Degree Name

Doctor of Philosophy (PhD)

Advisor/Committee Chair

Mien-Chie Hung, Ph.D.

Committee Member

Zhen Fan, Ph.D.

Committee Member

Kapil Mehta, Ph.D.

Committee Member

Min Gyu Lee, Ph.D.

Committee Member

Rebecca Berdeaux, Ph.D.

Abstract

Sirtuin6 (SIRT6) is one of the members of the Sirtuin family and functions as a longevity assurance gene by promoting genomic stability. It also regulates various cancer-associated pathways and was recently established as a bonafide tumor suppressor in colon cancer. This suggests that SIRT6 is an attractive target for pharmacological activation in cancer treatment, and hence, identification of potential regulators of SIRT6 would be an important and critical contribution towards cancer treatment. Here, we show that AKT1 phosphorylates SIRT6 at Ser³³⁸ and induces MDM2-SIRT6 interaction, priming SIRT6 for degradation via the MDM2-dependent ubiquitin-proteasome pathway. Blocking SIRT6 Ser³³⁸ phosphorylation prevents its degradation by MDM2 and results in inhibition of cell proliferation and breast cancer tumorigenesis in vivo. In addition, knockdown of SIRT6 in trastuzumab-sensitive cells renders them resistant to trastuzumab whereas overexpression of phosphorylation defective SIRT6 mutant restores trastuzumab sensitivity in the resistant cells. Thus, activation or re-expression of SIRT6 has potential clinical application to overcome trastuzumab resistance.

Keywords

Sirtuin, AKT, kinase, trastuzumab, phosphorylation, MDM2, breast cancer