Screening of SIRT6 inhibitors and activators: A novel activator has an impact on breast cancer cells

Tenhunen, Jonna; Kučera, Tomáš; Huovinen, Marjo; Küblbeck, Jenni; Bisenieks, Egīls; Vı̄gante, Brigita; Ogle, Zaiga; Duburs, G.; Doležal, Martin; Moaddel, Ruin; Lahtela‐Kakkonen, Maija; Rahnasto-Rilla, Minna

doi:10.1016/j.biopha.2021.111452

Cited by 13 publications

(7 citation statements)

References 43 publications

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“…In vivo studies revealed the critical role of high SIRT6 levels in slowing down hepatic cancer at an early stage of its progression [ 66 ]. 4H-Chromen, an activator of SIRT6, has been studied in various breast cancer cells and demonstrated to decrease cell proliferation in TNBC cells [ 69 ]. In this work, like SIRT1, cancerous MCF7 and MDA-MB-231 cell line-derived sEVs exhibited higher enzymatic activity of SIRT6 than sEVs of the non-cancerous MCF10A cell line.…”

Section: Discussionmentioning

confidence: 99%

Phosphoproteomic Analysis of Breast Cancer-Derived Small Extracellular Vesicles Reveals Disease-Specific Phosphorylated Enzymes

Hüttmann

Poolsup

et al. 2022

Biomedicines

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Small membrane-derived extracellular vesicles have been proposed as participating in several cancer diseases, including breast cancer (BC). We performed a phosphoproteomic analysis of breast cancer-derived small extracellular vesicles (sEVs) to provide insight into the molecular and cellular regulatory mechanisms important for breast cancer tumor progression and metastasis. We examined three cell line models for breast cancer: MCF10A (non-malignant), MCF7 (estrogen and progesterone receptor-positive, metastatic), and MDA-MB-231 (triple-negative, highly metastatic). To obtain a comprehensive overview of the sEV phosphoproteome derived from each cell line, effective phosphopeptide enrichment techniques IMAC and TiO2, followed by LC-MS/MS, were performed. The phosphoproteome was profiled to a depth of 2003 phosphopeptides, of which 207, 854, and 1335 were identified in MCF10A, MCF7, and MDA-MB-231 cell lines, respectively. Furthermore, 2450 phosphorylation sites were mapped to 855 distinct proteins, covering a wide range of functions. The identified proteins are associated with several diseases, mostly related to cancer. Among the phosphoproteins, we validated four enzymes associated with cancer and present only in sEVs isolated from MCF7 and MDA-MB-231 cell lines: ATP citrate lyase (ACLY), phosphofructokinase-M (PFKM), sirtuin-1 (SIRT1), and sirtuin-6 (SIRT6). With the exception of PFKM, the specific activity of these enzymes was significantly higher in MDA-MB-231 when compared with MCF10A-derived sEVs. This study demonstrates that sEVs contain functional metabolic enzymes that could be further explored for their potential use in early BC diagnostic and therapeutic applications.

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Section: Discussionmentioning

confidence: 99%

Phosphoproteomic Analysis of Breast Cancer-Derived Small Extracellular Vesicles Reveals Disease-Specific Phosphorylated Enzymes

Hüttmann

Poolsup

et al. 2022

Biomedicines

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“…4H-chromen was discovered in a recent study (Tenhunen et al, 2021) from a virtual screening campaign and was found to be a potent and selective activator for the SIRT6-catalyzed deacetylation reaction over the SIRT6catalyzed demyristoylation reaction, as also indicated in Figure 3. The putative binding site of 4H-chromen on SIRT6 suggested by molecular modeling studies partially overlaps with the N ε -myristoyl-lysine substrate's myristoyl chain binding site, which could explain the observed slight inhibition of 4H-chromen against the SIRT6 demyristoylase activity.…”

Section: Sirt6-catalyzed Deacetylation Reactionmentioning

confidence: 86%

The (patho)physiological roles of the individual deacylase activities of a sirtuin

Zheng

2024

Chem Biol Drug Des

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Since the discovery of the sirtuin family founding member (i.e., the yeast silent information regulator 2 (sir2) protein) in 2000, more and more sirtuin proteins have been identified and are currently known to be present in organisms from all the three kingdoms of life (i.e., bacteria, archaea, and eukarya). Seven sirtuin proteins have been identified in mammals including humans, that is, SIRT1/2/3/4/5/6/7. Sirtuin proteins are a class of enzymes with primary catalytic activity being the β‐nicotinamide adenine dinucleotide (β‐NAD+ or NAD+)‐dependent deacylation from the Nε‐acyl‐lysine residues on cellular proteins. Many sirtuins (e.g., human SIRT1/2/3/4/5/6/7) have been found to each possess multiple individual deacylase activities acting on Nε‐acyl‐lysine substrates with different acyl groups ranging from the simple formyl and acetyl to the more complex groups like succinyl and myristoyl; however, our current knowledge on the (patho)physiological roles of these individual deacylase activities is still limited, which could be due to the currently still thin research toolbox for investigation (i.e., the deacylase‐selective sirtuin mutant and inhibitor/activator). In this article, an updated account on the subject matter will be presented with biochemical and medicinal chemistry perspectives.

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“…Given the reported tumor suppressor activity of SIRT6, it is attractive to imagine compounds that could selectively activate SIRT6 through interactions with the hydrophobic groove. Indeed, multiple studies have identified compounds able to activate SIRT6 deacetylation activity (You et al, 2017(You et al, , 2019Tenhunen et al, 2021). Crystal structures consistently reveal SIRT6 activating compounds bound in the hydrophobic groove.…”

Section: Sirt6mentioning

confidence: 98%

Lysine Fatty Acylation: Regulatory Enzymes, Research Tools, and Biological Function

Komaniecki

Lin

2021

Front. Cell Dev. Biol.

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Post-translational acylation of lysine side chains is a common mechanism of protein regulation. Modification by long-chain fatty acyl groups is an understudied form of lysine acylation that has gained increasing attention recently due to the characterization of enzymes that catalyze the addition and removal this modification. In this review we summarize what has been learned about lysine fatty acylation in the approximately 30 years since its initial discovery. We report on what is known about the enzymes that regulate lysine fatty acylation and their physiological functions, including tumorigenesis and bacterial pathogenesis. We also cover the effect of lysine fatty acylation on reported substrates. Generally, lysine fatty acylation increases the affinity of proteins for specific cellular membranes, but the physiological outcome depends greatly on the molecular context. Finally, we will go over the experimental tools that have been used to study lysine fatty acylation. While much has been learned about lysine fatty acylation since its initial discovery, the full scope of its biological function has yet to be realized.

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Screening of SIRT6 inhibitors and activators: A novel activator has an impact on breast cancer cells

Cited by 13 publications

References 43 publications

Phosphoproteomic Analysis of Breast Cancer-Derived Small Extracellular Vesicles Reveals Disease-Specific Phosphorylated Enzymes

Phosphoproteomic Analysis of Breast Cancer-Derived Small Extracellular Vesicles Reveals Disease-Specific Phosphorylated Enzymes

The (patho)physiological roles of the individual deacylase activities of a sirtuin

Lysine Fatty Acylation: Regulatory Enzymes, Research Tools, and Biological Function

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