Dataset Information

SIRT6 phosphorylation - MDM2-mediated degradation of SIRT6 phosphorylated by AKT1 promotes tumorigenesis and trastuzumab resistance in breast cancer

ABSTRACT: Sirtuin 6 (SIRT6) is associated with longevity and was recently established as a tumor suppressor. Hence, identifying the molecular regulators of SIRT6 might enable its activation therapeutically in cancer patients. We found that SIRT6 was phosphorylated by the kinase AKT1 at Ser338, which induces its interaction with and ubiquitination by MDM2, priming it for protease-dependent degradation. The survival of patients with breast cancers positively correlated with the abundance of SIRT6 and inversely correlated with the phosphorylation of SIRT6 at Ser338. In a large panel of breast tumor biopsies, SIRT6 abundance inversely correlated with the abundance of phosphorylated AKT. Inhibiting AKT or preventing SIRT6 phosphorylation by mutating Ser338 prevented the degradation of SIRT6 mediated by MDM2, suppressed the proliferation of breast cancer cells in culture, and inhibited the growth of breast tumor xenografts in mice. Overexpressing MDM2 decreased the abundance of SIRT6 in cells, whereas overexpressing an E3 ligase-deficient MDM2 or knocking down endogenous MDM2 increased SIRT6 abundance. Knocking down SIRT6 decreased the sensitivity of a breast cancer cell line to trastuzumab, whereas overexpression of a non-phosphorylatable SIRT6 mutant increased trastuzumab sensitivity in a resistant subculture. Thus, stabilizing SIRT6 may be a clinical strategy for overcoming trastuzumab resistance in breast cancer patients.

INSTRUMENT(S): Q TRAP

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Permanent Cell Line Cell, Hela Cell

DISEASE(S): Breast Cancer

SUBMITTER: Umadevi Thirumurthi

LAB HEAD: Mien-Chie Hung

PROVIDER: PXD001154 | Pride | 2016-07-06

REPOSITORIES: Pride

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Publications

MDM2-mediated degradation of SIRT6 phosphorylated by AKT1 promotes tumorigenesis and trastuzumab resistance in breast cancer.

Thirumurthi Umadevi U Shen Jia J Xia Weiya W LaBaff Adam M AM Wei Yongkun Y Li Chia-Wei CW Chang Wei-Chao WC Chen Chung-Hsuan CH Lin Hui-Kuan HK Yu Dihua D Hung Mien-Chie MC

Science signaling 20140729 336

Sirtuin 6 (SIRT6) is associated with longevity and is also a tumor suppressor. Identification of molecular regulators of SIRT6 might enable its activation therapeutically in cancer patients. In various breast cancer cell lines, we found that SIRT6 was phosphorylated at Ser(338) by the kinase AKT1, which induced the interaction and ubiquitination of SIRT6 by MDM2, targeting SIRT6 for protease-dependent degradation. The survival of breast cancer patients positively correlated with the abundance of ...[more]

PMID: 25074979

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Project description:Purpose: The complete understanding of how genetic and epigenetic components control beta cell differentiation and function is key to the discovery of novel therapeutic approaches to prevent beta cell dysfunction and failure in the progression of type 2 diabetes. Our goal was to elucidate the role of histone deacetylase SIRT6 in beta-cell development and homeostasis. Methods: The Sirt6 endocrine progenitor cell conditional knockout (EKO) and beta-cell-specific knockout (BKO) mice were generated using the Cre-loxP system. Mice were assayed for islet morphology, glucose tolerance, glucose-stimulated insulin secretion, and susceptibility to streptozotocin. Transcriptional regulatory functions of SIRT6 in primary islets were evaluated by RNA-seq analysis. RT-qPCR and immunoblot were used to verify and investigate the gene expression changes. Chromatin occupancies of SIRT6, H3K9Ac, H3K56Ac, and active RNA Polymerase II were evaluated by chromatin immunoprecipitation. Results: Deletion of Sirt6 in pancreatic endocrine progenitor cells did not affect endocrine morphology, beta cell mass, or insulin production, but did result in glucose intolerance and defective glucose-stimulated insulin secretion in mice. Conditional deletion of Sirt6 in adult beta cells reproduced the insulin secretion defect. Loss of Sirt6 resulted in aberrant upregulation of TXNIP. SIRT6 deficiency led to increased accumulations of H3K9Ac, H3K56Ac, and active RNA polymerase II at the promoter region of Txnip. SIRT6-deficient beta cells exhibited a time-dependent increase of H3K9Ac, H3K56Ac, and TXNIP levels. Furthermore, beta-cell-specific SIRT6 deficient mice showed increased sensitivity to streptozotocin. Conclusions: Our results reveal that SIRT6 suppresses Txnip expression in beta-cells via deacetylation of histone H3 and plays a critical role in maintaining beta-cell function and viability. Agents that preserve SIRT6 activity may be beneficial for preventing the progression of type 2 diabetes.

Dataset Information

SIRT6 phosphorylation - MDM2-mediated degradation of SIRT6 phosphorylated by AKT1 promotes tumorigenesis and trastuzumab resistance in breast cancer

Publications

MDM2-mediated degradation of SIRT6 phosphorylated by AKT1 promotes tumorigenesis and trastuzumab resistance in breast cancer.

Similar Datasets

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