HALTING THE NAD+-DEPENDENT DEACETYLASE SIRT6 UNVEILS SPLICEOSOME DEREGULATION AS EXPLOITABLE VULNERABILITY FOR AGGRESSIVE MYELOMA
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PROVIDER: PRJNA869925 | ENA |
REPOSITORIES: ENA
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Project description:Epigenetic defects play a major role in tumors, by promoting aggressiveness, drug resistance and disease progression. Targeting enzymes responsible for these changes holds promise but the knowledge-gap and lack of selective inhibitors severely hampers their clinical use. Recently, we found that Multiple Myeloma (MM) cells exhibit high level of NAD+-dependent deacetylase SIRT6 as an adaptive response to their intrinsic genomic instability. Here we focus on splicing-related events resulting as the most enriched pathways among MM patients with high SIRT6 levels. CoMMpass dataset analysis confirmed the prognostic role of SIRT6 in MM, with its presence correlating with poor outcome and aggressiveness. Transcriptome analysis of SIRT6-depleted MM cells indicated spliceosome perturbation as critical: chemical and genetic approaches resulted in enhanced anti-MM activity of spliceosome modulator Sudamycin D6 (SD6) thus supporting RNA splicing deregulation as vulnerability for these cells. Spliceosome is a therapeutic weakness for MYC-driven cancer, as such we found that while c-MYC oncogene loss shows resistance, its re-expression enhances efficacy of tested strategy. A direct role for SIRT6 on splicing factors genes was also demonstrated using ChIP-seq analyses. Overall, the dysregulated spliceosome activity triggered by epigenetic machinery blocking represents a novel therapeutic strategy for poor-prognosis subset of MM patients overexpressing c-MYC
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2010-06-08 | E-GEOD-21965 | biostudies-arrayexpress
Project description:c-MYC (MYC) overexpression or hyperactivation is one of the most common drivers of human cancer. Despite intensive study, the MYC oncogene remains recalcitrant to therapeutic inhibition. Like other classic oncogenes, hyperactivation of MYC leads to collateral stresses onto cancer cells, suggesting that tumors harbor unique vulnerabilities arising from oncogenic activation of MYC. Herein, we discover the spliceosome as a new target of oncogenic stress in MYC-driven cancers. We identify BUD31 as a MYC-synthetic lethal gene, and demonstrate that BUD31 is a splicing factor required for the assembly and catalytic activity of the spliceosome. Core spliceosomal factors (SF3B1, U2AF1, and others) associate with BUD31 and are also required to tolerate oncogenic MYC. Notably, MYC hyperactivation induces an increase in total pre-mRNA synthesis, suggesting an increased burden on the core spliceosome to process pre-mRNA. In contrast to normal cells, partial inhibition of the spliceosome in MYC-hyperactivated cells leads to global intron retention, widespread defects in pre-mRNA maturation, and deregulation of many essential cell processes. Importantly, genetic or pharmacologic inhibition of the spliceosome in vivo impairs survival, tumorigenicity, and metastatic proclivity of MYC-dependent breast cancers. Collectively, these data suggest that oncogenic MYC confers a collateral stress on splicing and that components of the spliceosome may be therapeutic entry points for aggressive MYC-driven cancers. Examination of intron rentention in MYC-ER HMECs, in 4 conditions
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Project description: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.
2016-07-06 | PXD001154 | Pride
Project description:Chromatin remodeling proteins are frequently dysregulated in human cancer, yet little is known about how they control tumorigenesis. Here, we uncover an epigenetic program mediated by the NAD+-dependent histone deacetylase Sirtuin 6 (SIRT6) that is critical for suppression of pancreatic ductal adenocarcinoma (PDAC), one of the most lethal malignancies. SIRT6 inactivation accelerates PDAC progression and metastasis via upregulation of Lin28b, a negative regulator of the let-7 microRNA. SIRT6 loss results in histone hyperacetylation at the Lin28b promoter, Myc recruitment, and pronounced induction of Lin28b and downstream let-7 target genes, HMGA2, IGF2BP1 and IGF2BP3. This epigenetic program defines a distinct subset representing 30-40% of human PDAC, characterized by poor prognosis and an exquisite dependence on Lin28b for tumor growth. Thus, we identify SIRT6 as an important PDAC tumor suppressor, and uncover the Lin28b pathway as a potential therapeutic target in a molecularlydefined PDAC subset. ChIP-Seq experiments to examine H3K56ac histone modifications in murine PDAC cells that are Sirt6 wild type (WT), Sirt6 knock-out (KO), and Sirt6 KO cells engineered to express Sirt6 WT (Sirt6 KO + Sirt6 WT Restored).
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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.
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