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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 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 SIRT6 and inversely correlated with the phosphorylation of SIRT6 at Ser(338). In a panel of breast tumor biopsies, SIRT6 abundance inversely correlated with the abundance of phosphorylated AKT. Inhibiting AKT or preventing SIRT6 phosphorylation by mutating Ser(338) 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. Trastuzumab (known as Herceptin) is a drug that targets a specific receptor common in some breast cancers, and knocking down SIRT6 increased the survival of a breast cancer cell exposed to trastuzumab. Overexpression of a nonphosphorylatable SIRT6 mutant increased trastuzumab sensitivity in a resistant breast cancer cell line. Thus, stabilizing SIRT6 may be a clinical strategy for overcoming trastuzumab resistance in breast cancer patients.

SUBMITTER: Thirumurthi U

PROVIDER: S-EPMC4161976 | biostudies-literature | 2014 Jul

REPOSITORIES: biostudies-literature

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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:BackgroundSirtuin 6 (SIRT6) is a NAD+-dependent deacetylase with key roles in cell metabolism. High SIRT6 expression is associated with adverse prognosis in breast cancer (BC) patients. However, the mechanisms through which SIRT6 exerts its pro-oncogenic effects in BC remain unclear. Here, we sought to define the role of SIRT6 in BC cell metabolism and in mouse polyoma middle T antigen (PyMT)-driven mammary tumors.MethodsWe evaluated the effect of a heterozygous deletion of Sirt6 on tumor latency and survival of mouse mammary tumor virus (MMTV)-PyMT mice. The effect of SIRT6 silencing on human BC cell growth was assessed in MDA-MB-231 xenografts. We also analyzed the effect of Sirt6 heterozygous deletion, of SIRT6 silencing, and of the overexpression of either wild-type (WT) or catalytically inactive (H133Y) SIRT6 on BC cell pyruvate dehydrogenase (PDH) expression and activity and oxidative phosphorylation (OXPHOS), including respiratory complex activity, ATP/AMP ratio, AMPK activation, and intracellular calcium concentration.ResultsThe heterozygous Sirt6 deletion extended tumor latency and mouse survival in the MMTV-PyMT mouse BC model, while SIRT6 silencing slowed the growth of MDA-MB-231 BC cell xenografts. WT, but not catalytically inactive, SIRT6 enhanced PDH expression and activity, OXPHOS, and ATP/AMP ratio in MDA-MB-231 and MCF7 BC cells. Opposite effects were obtained by SIRT6 silencing, which also blunted the expression of genes encoding for respiratory chain proteins, such as UQCRFS1, COX5B, NDUFB8, and UQCRC2, and increased AMPK activation in BC cells. In addition, SIRT6 overexpression increased, while SIRT6 silencing reduced, intracellular calcium concentration in MDA-MB-231 cells. Consistent with these findings, the heterozygous Sirt6 deletion reduced the expression of OXPHOS-related genes, the activity of respiratory complexes, and the ATP/AMP ratio in tumors isolated from MMTV-PyMT mice.ConclusionsVia its enzymatic activity, SIRT6 enhances PDH expression and activity, OXPHOS, ATP/AMP ratio, and intracellular calcium concentration, while reducing AMPK activation, in BC cells. Thus, overall, SIRT6 inhibition appears as a viable strategy for preventing or treating BC.

Project description:BACKGROUND:Sirtuin 6 (Sirt6) is a highly conserved ADP-ribosylase and NAD+ dependent deacylase, involved in broad cellular processes. This molecule possesses contradictory roles in carcinogenesis, as it has been documented to both suppressing and augmenting tumor growth. This project aimed to explore the expression and functions of Sirt6 in diffuse large B-cell lymphoma (DLBCL), especially with regards to the regulatory role of OSS_128167, a novel small molecular inhibitor targeting Sirt6. METHODS:Immunohistochemistry (IHC) was conducted to assess the expression of Sirt6 on paraffin-embedded tissues. Microarray dataset GSE32918 and GSE83632 were obtained from Gene Expression Omnibus and survival analysis was performed. Lentivirus vectors either encoding shSirt6, lvSirt6 or empty lentiviral vector were stably transfected into DLBCL cells. LY1 cell transfected with shSirt6 were performed RNA-sequencing (RNA-seq) analysis, functional enrichment analyses of gene ontology (GO) and gene set enrichment analysis (GSEA). DLBCL cells were subcutaneously injected to SCID beige mice to establish xenograft models. RESULTS:Sirt6 is found to be overexpressed in DLBCL, and is related to poor prognosis. Sirt6-deprived DLBCL cells displayed augmented sensitivity towards chemotherapy, higher rates of apoptosis, dysfunctional cell proliferation, and arrested cell cycle progression between the G2 and M phases. Selective OSS_128167-mediated Sirt6 blockage resulted in similar anti-lymphoma effects when compared to Sirt6 knocked-down DLBCL cells. PI3K signaling along with phosphorylation of its downstream targets was reduced upon Sirt6 downregulation. Xenograft models subjected to either OSS_128167 treatment or Sirt6-knockdown showed suppressed tumor growth and lower Ki-67 level. CONCLUSIONS:These findings provide mechanistic insights into the oncogenic activity of Sirt6 in DLBCL for the first time and highlighted the potency of OSS_128167 for novel therapeutic strategies in DLBCL.

Dataset Information

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.

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