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SIRT4 controls acetyl-CoA synthesis to promote stemness and invasiveness of hepatocellular carcinoma through deacetylating MCCC2

ABSTRACT: The mitochondria sirtuin 4 (SIRT4) is well-known as a tumor suppressor by controlling several metabolic pathways, although it is highly expressed in certain cancers including hepatocellular carcinoma (HCC). Here, we reported that SIRT4 was highly expressed in a subset of the voltage-gated calcium channel α2δ1 subunit-positive HCC tumor-initiating cells (TIC), and was upregulated by α2δ1-mediated calcium signaling. Furthermore, SIRT4 is functionally sufficient and indispensable to promote TIC properties and invasiveness of HCC cells by directly deacetylating the leucine catabolism pathway enzyme－3-methylcrotonyl-CoA carboxylase 2 (MCCC2) at K269, leading to the formation of a stable MCCC1/MCCC2 complex with robust MCCC enzymatic activity to produce increased levels of acetyl-CoA, which subsequently resulted in increased levels of H3K27 acetylation and stem cell-like properties at tested doses≤2 µM. Interestingly, the expression of SIRT4 in HCC tissues was predictive of poor prognosis of the patients. These findings identify SIRT4 as an oncogene to promote stemness and invasiveness by controlling the production of acetyl-CoA, linking α2δ1-mediated calcium signaling to SIRT4-mediated epigenetic regulation of the stem cell-like properties which hold significant potential for the development of innovative therapeutic strategies targeting HCC TICs.

ORGANISM(S): Homo sapiens

PROVIDER: GSE279886 | GEO | 2024/12/31

REPOSITORIES: GEO

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SIRT4 controls acetyl-CoA synthesis to promote stemness and invasiveness of hepatocellular carcinoma through deacetylating MCCC2 [RNA-seq]

Project description:The mitochondria sirtuin 4 (SIRT4) is well-known as a tumor suppressor by controlling several metabolic pathways, although it is highly expressed in certain cancers including hepatocellular carcinoma (HCC). Here, we reported that SIRT4 was highly expressed in a subset of the voltage-gated calcium channel α2δ1 subunit-positive HCC tumor-initiating cells (TIC), and was upregulated by α2δ1-mediated calcium signaling. Furthermore, SIRT4 is functionally sufficient and indispensable to promote TIC properties and invasiveness of HCC cells by directly deacetylating the leucine catabolism pathway enzyme－3-methylcrotonyl-CoA carboxylase 2 (MCCC2) at K269, leading to the formation of a stable MCCC1/MCCC2 complex with robust MCCC enzymatic activity to produce increased levels of acetyl-CoA, which subsequently resulted in increased levels of H3K27 acetylation and stem cell-like properties at tested doses≤2 µM. Interestingly, the expression of SIRT4 in HCC tissues was predictive of poor prognosis of the patients. These findings identify SIRT4 as an oncogene to promote stemness and invasiveness by controlling the production of acetyl-CoA, linking α2δ1-mediated calcium signaling to SIRT4-mediated epigenetic regulation of the stem cell-like properties which hold significant potential for the development of innovative therapeutic strategies targeting HCC TICs.

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SIRT4 controls acetyl-CoA synthesis to promote stemness and invasiveness of hepatocellular carcinoma through deacetylating MCCC2

Project description:SIRT4 controls acetyl-CoA synthesis to promote stemness and invasiveness of hepatocellular carcinoma through deacetylating MCCC2

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SIRT4 KO livers microarray

Project description:Sirtuins are a family of protein deacetylases, deacylases, and ADP-ribosyltransferases that regulate life span, control the onset of numerous age-associated diseases, and mediate metabolic homeostasis. We have uncovered a novel role for the mitochondrial sirtuin SIRT4 in the regulation of hepatic lipid metabolism during changes in nutrient availability. We show that SIRT4 levels decrease in the liver during fasting and that SIRT4 null mice display increased expression of hepatic peroxisome proliferator activated receptor (PPAR ) target genes associated with fatty acid catabolism. Accordingly, primary hepatocytes from SIRT4 knockout (KO) mice exhibit higher rates of fatty acid oxidation than wild-type hepatocytes, and SIRT4 overexpression decreases fatty acid oxidation rates. The enhanced fatty acid oxidation observed in SIRT4 KO hepatocytes requires functional SIRT1, demonstrating a clear cross talk between mitochondrial and nuclear sirtuins. Thus, SIRT4 is a new component of mitochondrial signaling in the liver and functions as an important regulator of lipid metabolism. SIRT4 knockout (KO) and wild-type (WT) littermates (male; n 6 per genotype; 7- to 8-month-old littermates) were sacrificed after a 16-h overnight fast. Samples were individually hybridized on Affymetrix Mouse Genome 430 2.0 GeneChips by the Biopolymers Facility (Harvard Medical School).

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SIRT4 controls acetyl-CoA synthesis to promote stemness and invasiveness of hepatocellular carcinoma through deacetylating MCCC2 [RNA-seq]

Project description:SIRT4 controls acetyl-CoA synthesis to promote stemness and invasiveness of hepatocellular carcinoma through deacetylating MCCC2 [RNA-seq]

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SIRT4 KO livers microarray

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Nuclear Translocation of SIRT4 Mediates Deacetylation of U2AF2 to Modulate Renal Fibrosis Through Alternative Splicing-mediated Upregulation of CCN2

Project description:TGF-β stimulates CCN2 expression which in turn amplifies TGF-β signaling. This process promotes extracellular matrix production and accelerates the pathological progression of fibrotic diseases. Alternative splicing plays an important role in multiple disease development, while U2 small nuclear RNA auxiliary factor 2 (U2AF2) is an essential factor in the early steps of pre-mRNA splicing. However, the molecular mechanism underlying abnormal CCN2 expression upon TGF-β stimulation remains unclear. This study elucidates that SIRT4 acts as a master regulator for CCN2 expression in response to TGF-β by modulating U2AF2-mediated alternative splicing. Analyses of renal biopsy specimens from patients with CKD and mouse fibrotic kidney tissues revealed marked nuclear accumulation of SIRT4. The tubulointerstitial fibrosis was alleviated by global deletion or tubular epithelial cell (TEC)-specific knockout of Sirt4, and aggravated by adeno-associated virus-mediated SIRT4 overexpression in TECs. Furthermore, SIRT4 was found to translocate from the mitochondria to the cytoplasm through the BAX/BAK pore under TGF-β stimulation. In the cytoplasm, TGF-β activated the ERK pathway and induced the phosphorylation of SIRT4 at Ser36, which further promoted its interaction with importin α1 and subsequent nuclear translocation. In the nucleus, SIRT4 was found to deacetylate U2AF2 at K413, facilitating the splicing of CCN2 pre-mRNA to promote CCN2 protein expression. Importantly, exosomes containing anti-SIRT4 antibodies were found to effectively mitigate the UUO-induced kidney fibrosis in mice. Collectively, these findings indicated that SIRT4 plays a role in kidney fibrosis by regulating CCN2 expression via the pre-mRNA splicing.

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Project description:We profile gene expression with or without SIRT4 overexpression in pancreatic cancer cell line CAPAN-2 to find the different genes and pathways regulated by SIRT4.

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Amino Acids Downregulate SIRT4 to Detoxify Ammonia through the Urea Cycle

Project description:Ammonia production via glutamate dehydrogenase is inhibited by SIRT4, a sirtuin that displays both amidase and non-amidase activities. The processes underlying the regulation of ammonia removal by amino acids remain unclear. Here, we report that SIRT4 acts as a decarbamylase that responds to amino acid sufficiency and regulates ammonia removal. Amino acids promote lysine 307 carbamylation (OTCCP-K307) of ornithine transcarbamylase (OTC), which activates OTC and the urea cycle. Proteomic and interactome screening identified OTC as a substrate of SIRT4. SIRT4 decarbamylates OTCCP-K307 and inactivates OTC in a NAD+-dependent manner. SIRT4 expression was transcriptionally upregulated by the amino acid insufficiency-activated GCN2–eIF2a–ATF4 axis. SIRT4 knockout in cultured cells caused higher OTCCP-K307 levels, activated OTC, elevated urea cycle intermediates, and urea production via amino acid catabolism. Sirt4 ablation decreased mouse blood ammonia levels and ameliorated CCl4-induced hepatic encephalopathy phenotypes. We reveal that SIRT4 safeguards cellular ammonia toxicity during amino acid catabolism.

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Downregulation of miR-15b is associated with increased SIRT4 expression in premature senescence and photoaging of the skin

Project description:Sirtuins are deacetylases or ADP-ribosyltransferases which are implicated in multiple pathways involved in metabolism and life-span regulation. Here, we link the mitochondrial sirtuin SIRT4, which overexpression negatively impacts on mitochondrial oxidative capacity, with premature senescence and skin aging. Accordingly, SIRT4 mRNA levels were significantly increased in vitro in human dermal fibroblasts after repetitive UVB exposure or in senescence triggered by mitotic spindle stress or ionizing radiation. Similarly, analysis of SIRT4 expression in vivo in human skin revealed upregulation of SIRT4 mRNA levels in the dermal compartment of photaged skin as compared with the dermis of intrinsically aged skin. In all our in vitro models, upregulation of SIRT4 expression was associated with decreased levels of miR-15b. Also, in human skin, highest copy numbers of miR-15b mRNA were detected in the epidermis, and epidermal expression was significantly reduced in photoaged skin as compared with intrinsically aged skin. Reduced miR-15b expression is most likely causally linked to increased SIRT4 expression because we found that (i) miR-15b displays a conserved and direct binding site within the 3'-untranslated region of the SIRT4 gene as demonstrated by luciferase reporter assays and (ii) transfection of oligonucleotides mimicking miR-15b function was sufficient to prevent SIRT4 upregulation in senescent cells in vitro. Thus, we propose that miR-15b acts as a negative regulator of SIRT4 expression to antagonize mitochondrial dysfunction and hence cellular senescence as well as tissue aging, in particular photoaging of the skin.

2016-06-08 | GSE45729 | GEO

SIRT4 Is a Lysine Deacylase that Controls Leucine Metabolism and Insulin Secretion

Project description:Sirtuins are NAD+-dependent protein deacylases that regulate several aspects of metabolism and aging. In contrast to the other mammalian sirtuins, the primary enzymatic activity of mitochondrial sirtuin 4 (SIRT4) and its overall role in metabolic control has remained enigmatic. Using a combination of phylogenetics, structural biology, and enzymology, we show that SIRT4 removes three acyl moieties from lysine residues – methylglutaryl(MG)-, hydroxymethylglutaryl(HMG)-, and 3-methylglutaconyl(MGc)-lysine. The metabolites leading to these post-translational modifications are intermediates in leucine oxidation, and we show a primary role for SIRT4 in controlling this pathway in mice. Furthermore, we find that dysregulated leucine metabolism in SIRT4KO mice leads to elevated basal and stimulated insulin secretion, which progressively develops into glucose intolerance and insulin resistance. These findings identify a robust enzymatic activity for SIRT4, uncover a mechanism controlling branched-chain amino acid flux, and position SIRT4 as a crucial player maintaining insulin secretion and glucose homeostasis during aging. From Anderson et. al. Cell Metabolism, 2017.

2017-04-05 | PXD005896 | Pride

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