Targeting DNA damage repair functions of two histone deacetylases, HDAC8 and SIRT6, sensitizes acute myeloid leukemia to NAMPT inhibition
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ABSTRACT:
PROVIDER: PRJNA681917 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR13178269.fastq.gz | Fastqsanger.gz | |||
| SRR13178270.fastq.gz | Fastqsanger.gz | |||
| SRR13178271.fastq.gz | Fastqsanger.gz |
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Project description:PurposeNicotinamide phosphoribosyltransferase (NAMPT) inhibitors (NAMPTi) are currently in development, but may be limited as single-agent therapy due to compound-specific toxicity and cancer metabolic plasticity allowing resistance development. To potentially lower the doses of NAMPTis required for therapeutic benefit against acute myeloid leukemia (AML), we performed a genome-wide CRISPRi screen to identify rational disease-specific partners for a novel NAMPTi, KPT-9274.Experimental designCell lines and primary cells were analyzed for cell viability, self-renewal, and responses at RNA and protein levels with loss-of-function approaches and pharmacologic treatments. In vivo efficacy of combination therapy was evaluated with a xenograft model.ResultsWe identified two histone deacetylases (HDAC), HDAC8 and SIRT6, whose knockout conferred synthetic lethality with KPT-9274 in AML. Furthermore, HDAC8-specific inhibitor, PCI-34051, or clinical class I HDAC inhibitor, AR-42, in combination with KPT-9274, synergistically decreased the survival of AML cells in a dose-dependent manner. AR-42/KPT-9274 cotreatment attenuated colony-forming potentials of patient cells while sparing healthy hematopoietic cells. Importantly, combined therapy demonstrated promising in vivo efficacy compared with KPT-9274 or AR-42 monotherapy. Mechanistically, genetic inhibition of SIRT6 potentiated the effect of KPT-9274 on PARP-1 suppression by abolishing mono-ADP ribosylation. AR-42/KPT-9274 cotreatment resulted in synergistic attenuation of homologous recombination and nonhomologous end joining pathways in cell lines and leukemia-initiating cells.ConclusionsOur findings provide evidence that HDAC8 inhibition- or shSIRT6-induced DNA repair deficiencies are potently synergistic with NAMPT targeting, with minimal toxicity toward normal cells, providing a rationale for a novel-novel combination-based treatment for AML.
| S-EPMC8054771 | biostudies-literature
Project description:CRISPR knockout screening on MOLM-13 cells with KPT-9274
2021-01-27 | GSE162473 | GEO
Project description:Endogenous expression of inactive lysine deacetylases KDAC6 (HDAC6) and KDAC8 (HDAC8)
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Project description:The significant increase in the human life-span during the last century confronts us with great medical challenges. To answer them, one must understand and control the mechanisms that determine healthy ageing. The highly conserved sirtuin deacetylases were shown to regulate life-span in lower organisms. Yet, the role of mammalian sirtuins, SIRT1 to 7, in regulating life-span is currently unclear. Here, we show that in SIRT6 transgenic mice (Sirt6-tg), the males but not the females, have a significant increase in life-span. Gene expression analysis revealed significant differences for male Sirt6-tg in comparison to male wild-type mice. Transgenic males display lower serum IGF-1 levels, increased levels of IGFBP-1 and altered phosphorylation levels of major components of the IGF-1 pathway, a key factor in the regulation of life-span. This study is the first to show regulation of mammalian life-span by a sirtuin family member, and has important therapeutic implications for age-related diseases.
2012-04-01 | E-MTAB-871 | biostudies-arrayexpress
Project description:As a member of class III histone deacetylases, Sirt6 has various functions including regulation of genomic stability, DNA repair, cancer, metabolism and ageing.Deficiency of Sirt6 is lethal and causes brain development redardation. We generated Emx1-cre induced Sirt6 conditional knockout mice model and found that Sirt6 deficiency promoted self-renew of neural precursor cells (NPCs) and inhibited differentiation. This result promotes understanding of the role of Sirt6 in brain development and NPCs’ fate determination and provides clues to explain the generality and difference between species.
2024-01-31 | GSE236460 | GEO
Project description:HDAC3 and HDAC8 are members of class I deacetylases involved in several biological mechanisms and represent a highly sought-after therapeutic target for drug development. It is historically challenging to develop selective deacetylase inhibitors due to their conserved catalytic domains. HDAC3 also has deacetylase-independent activity, which cannot be blocked by conventional enzymatic inhibitors. Recent advance in proteolysis-targeting chimeras (PROTACs) provides an opportunity to eliminate the whole protein selectively, abolishing both enzymatic and scaffolding function. Here, we report a novel HDAC3/8 dual degrader YX968 that induces highly potent, rapid, and selective degradation of both HDAC3 and HDAC8 without trigging pan-HDAC inhibitory effects. Unbiased quantitative proteomics experiments further confirmed its high selectivity. This dual-specific degrader specifically ablates cellular pathways attributed to HDAC3 and HDAC8 and exhibits high potency in killing cancer cells. YX968 represents a new probe for dissecting the complex biological functions of HDAC3 and HDAC8.
2023-07-18 | GSE211758 | GEO
Project description:To find the SIRT6 and SIRT7 binding proteins, we expressed V5-tagged SIRT6 and SIRT7 and pulled down this protein with anti-V5 agarose affinity gel. Sirtuins are a family of NAD-dependent deacetylases which deacetylate not only histones but also a wide range of target proteins. Sirtuins are conserved from yeast to mammal, and are known to regulate many processes such as cellular metabolism, apoptosis, cellular senescence, cell cycle, and organism-level aging. Among the members of sirtuins showing different subcellular localization, SIRT1, SIRT6 and SIRT7 are localized in nucleus. Whereas many functions and interacting proteins of SIRT1 have been studied, functions of SIRT6 and SIRT7 are not extensively revealed yet. Since it is important to understand the molecular function of SIRT6 and SIRT7, we here aimed to identify interacting proteins in mammalian cells.<br>Extra primary submitter: <a href="mailto:nglee@postech.ac.kr" target="_top">Namgyu Lee</a>, Department of Life Sciences, Pohang University of Science and Technology, Pohang, 790-784, Republic of Korea<br>Lab head: <a href="mailto:kchoi@postech.ac.kr" target="_top">Kwan Yong Choi</a>, Department of Life Sciences and Division of Integrative Biosciences and Biotechnology, Pohang University of Science and Technology, Pohang, 790-784, Republ ic of Korea
2014-04-28 | PXD000159 | Pride
Project description:HDAC3 and HDAC8 are members of class I deacetylases involved in several biological mechanisms and represent a highly sought-after therapeutic target for drug development. It is historically challenging to develop selective deacetylase inhibitors due to their conserved catalytic domains. HDAC3 also has deacetylase-independent activity, which cannot be blocked by conventional enzymatic inhibitors. Recent advances in proteolysis-targeting chimeras (PROTACs) provides an opportunity to eliminate the whole protein selectively, abolishing both enzymatic and scaffolding functions. Here, we report a novel HDAC3/8 dual degrader YX968 that induces highly potent, rapid and selective degradation of both HDAC3 and HDAC8 without trigging pan-HDAC inhibitory effects. Unbiased quantitative proteomics experiments further confirmed its high selectivity. This dual-specific degrader specifically ablates cellular pathways attributed to HDAC3 and HDAC8 and exhibits high potency in killing cancer cells. YX968 represents a new probe for dissecting the complex biological functions of HDAC3 and HDAC8.
2023-07-18 | PXD040941 | Pride
Project description:This SuperSeries is composed of the following subset Series: GSE13206: Human shSIRT6 TNF-alpha timecourse GSE13207: Mouse Sirt6-/- TNF-alpha timecourse GSE13208: Mouse Sirt6-/- tissues GSE13209: Mouse Sirt6-/- RelA+/- tissues Refer to individual Series
2010-06-24 | E-GEOD-13272 | biostudies-arrayexpress
Project description:Obesity is a major health burden. Adipogenesis, the proliferation and differentiation of pree-adipocytes in mature adipocytes, could be a potential therapeutic approach for obesity. Deficiency of SIRT6, a member of the sirtuin family of nicotinamide adenine dinucleotide (NAD)+-dependent protein deacetylases, blocks adipogenesis. New allelic variants of SIRT6 (N308K/A313S) were recently associated with the longevity in Ashkenazi Jews. In this study, we aimed to clarify how these new centenarian-associated SIRT6 genetic variants affect adipogenesis at the transcriptional and epigenetic level. Overexpression of centenarian-associated SIRT6 mutant increased adipogenic differentiation to a similar extent compared to the WT form. However, it triggered distinct histone PTM profiles in mature adipocytes, with significantly higher acetylation levels, and activated divergent transcriptional programs, including those dependent on signaling related to the sympathetic innervation and to PI3K pathway. 3T3-L1 mature adipocytes overexpressing SIRT6 N308K/A313S displayed increased insulin sensitivity in a neuropeptide Y (NPY)-dependent manner.
2024-08-10 | PXD051761 | Pride