Dual Tumor Suppressor and Tumor Promoter Action of Sirtuins in Determining Malignant Phenotype

Carafa, Vincenzo; Altucci, Lucia; Nebbioso, Angela

doi:10.3389/fphar.2019.00038

Cited by 135 publications

(108 citation statements)

References 170 publications

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“…Sirtuins have been implicated in different cellular processes, being key epigenetic modulators of EMT activation and maintenance [23,24]. Interestingly, SIRT1 has been shown to play a dual role in tumorigenesis, acting either as an oncogene or tumor suppressor gene according to the tumor context [23,27].…”

Section: Discussionmentioning

confidence: 99%

Lactate Increases Renal Cell Carcinoma Aggressiveness through Sirtuin 1-Dependent Epithelial Mesenchymal Transition Axis Regulation

Miranda‐Gonçalves

Lameirinhas

Macedo-Silva

et al. 2020

Cells

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Background: Renal cell carcinoma (RCC) displays a glycolytic phenotype (Warburg effect). Increased lactate production, impacting on tumor biology and microenvironment modulation, has been implicated in epigenetic mechanisms' regulation, leading to histone deacetylases inhibition. Thus, in-depth knowledge of lactate's impact on epigenome regulation of highly glycolytic tumors might allow for new therapeutic strategies. Herein, we investigated how extracellular lactate affected sirtuin 1 activity, a class III histone deacetylase (sirtuins, SIRTs) in RCC. Methods: In vitro and in vivo interactions between lactate and SIRT1 in RCC were investigated in normal kidney and RCC cell lines. Finally, SIRT1 and N-cadherin immunoexpression was assessed in human RCC and normal renal tissues. Results: Lactate inhibited SIRT1 expression in normal kidney and RCC cells, increasing global H3 and H3K9 acetylation. Cells exposed to lactate showed increased cell migration and invasion entailing a mesenchymal phenotype. Treatment with a SIRT1 inhibitor, nicotinamide (NAM), paralleled lactate effects, promoting cell aggressiveness. In contrast, alpha-cyano-4-hydroxycinnamate (CHC), a lactate transporter inhibitor, reversed them by blocking lactate transport. In vivo (chick chorioallantoic membrane (CAM) assay), lactate and NAM exposure were associated with increased tumor size and blood vessel recruitment, whereas CHC displayed the opposite effect. Moreover, primary RCC revealed N-cadherin upregulation whereas SIRT1 expression levels were downregulated compared to normal tissues. Conclusions: In RCC, lactate enhanced aggressiveness and modulated normal kidney cell phenotype, in part through downregulation of SIRT1, unveiling tumor metabolism as a promising therapeutic target.

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Section: Discussionmentioning

confidence: 99%

Lactate Increases Renal Cell Carcinoma Aggressiveness through Sirtuin 1-Dependent Epithelial Mesenchymal Transition Axis Regulation

Miranda‐Gonçalves

Lameirinhas

Macedo-Silva

et al. 2020

Cells

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“…The sirtuins (SIRTs), are a family of highly-conserved histone deacetylases (HDACs) that are differentially expressed in several human cancers, where they display both oncogenic and tumor-suppressive properties depending on cellular context and experimental conditions [97]. SIRTs have also been shown to regulate a wide variety of cellular processes beyond transcriptional repression in varied subcellular compartments and in different cell types [97]. SIRT6 is unique in its constitutive localization to chromatin [98] and has been shown to regulate many important pathways via epigenetic mechanisms, mainly histone deacetylation.…”

Section: Sirt1 Sirt6 and Metabolism Regulationmentioning

confidence: 99%

The Mitochondrial Protein VDAC1 at the Crossroads of Cancer Cell Metabolism: The Epigenetic Link

Amsalem

Arif

Shteinfer‐Kuzmine

et al. 2020

Cancers

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Carcinogenesis is a complicated process that involves the deregulation of epigenetics, resulting in cellular transformational events, such as proliferation, differentiation, and metastasis. Most chromatin-modifying enzymes utilize metabolites as co-factors or substrates and thus are directly dependent on such metabolites as acetyl-coenzyme A, S-adenosylmethionine, and NAD+. Here, we show that using specific siRNA to deplete a tumor of VDAC1 not only led to reprograming of the cancer cell metabolism but also altered several epigenetic-related enzymes and factors. VDAC1, in the outer mitochondrial membrane, controls metabolic cross-talk between the mitochondria and the rest of the cell, thus regulating the metabolic and energetic functions of mitochondria, and has been implicated in apoptotic-relevant events. We previously demonstrated that silencing VDAC1 expression in glioblastoma (GBM) U-87MG cell-derived tumors, resulted in reprogramed metabolism leading to inhibited tumor growth, angiogenesis, epithelial-mesenchymal transition and invasiveness, and elimination of cancer stem cells, while promoting the differentiation of residual tumor cells into neuronal-like cells. These VDAC1 depletion-mediated effects involved alterations in transcription factors regulating signaling pathways associated with cancer hallmarks. As the epigenome is sensitive to cellular metabolism, this study was designed to assess whether depleting VDAC1 affects the metabolism-epigenetics axis. Using DNA microarrays, q-PCR, and specific antibodies, we analyzed the effects of si-VDAC1 treatment of U-87MG-derived tumors on histone modifications and epigenetic-related enzyme expression levels, as well as the methylation and acetylation state, to uncover any alterations in epigenetic properties. Our results demonstrate that metabolic rewiring of GBM via VDAC1 depletion affects epigenetic modifications, and strongly support the presence of an interplay between metabolism and epigenetics.Cancers 2020, 12, 1031 2 of 25 cellular metabolic activity regulates transcriptional networks and cell-fate decisions via epigenetic programs involving metabolite-dependent effects on chromatin organization. Epigenetics refers to a change in chromatin that leads to the regulation of gene expression without alterations in the DNA sequence [6]. Epigenetic modifications include DNA methylation, and/or histone modifications by acetylation, ubiquitination, methylation, phosphorylation, sumoylation, glycosylation, and biotinylation, changes that play a critical role in many cellular processes [7][8][9][10][11][12][13]. The enzymes responsible for these modifications include histone acetyltransferases (HATs), histone deacetylases (HDACs), methyltransferases (KMTs), and demethylases (KDMs) [14][15][16].There is now an accumulation of evidence that the epigenome is sensitive to cellular metabolism and a link between metabolism and epigenetics [3][4][5][17][18][19] has been proposed, with epigenetics and gene transcription being influenced by products of metabolic pathways [...

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“…Recent overviews of the literature revealed that SIRT4, although first described as a metabolic tumor suppressor 37 , may display both tumor suppressor and oncogenic/cancer promoting activities, depending on the tumor type and checkpoint activating conditions 72,73 . Our data on the putative SIRT4-HDAC6-microtubule dynamics axis are rather consistent with an extramitochondrial tumor suppressor function of SIRT4.…”

Section: Discussionmentioning

confidence: 99%

Subcellular localization and mitotic interactome analyses identify SIRT4 as a centrosomally localized and microtubule associated protein

Bergmann

Lang

Bross

et al. 2020

Preprint

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The stress-inducible and senescence-associated tumor suppressor SIRT4, a member of the family of mitochondrial sirtuins (SIRT3, SIRT4, and SIRT5), regulates bioenergetics and metabolism via NAD + -dependent enzymatic activities. Next to the known mitochondrial location, we found that a fraction of endogenous or ectopically expressed SIRT4, but not SIRT3, is located at the mitotic spindle apparatus in the cytosol. Confocal spinning disk microscopy revealed that SIRT4 localizes during the cell cycle dynamically at centrosomes with an intensity peak in G2 and early mitosis.Moreover, SIRT4 binds to microtubules and interacts with structural (α,β-tubulin, -tubulin, TUBGCP2, TUBGCP3) and regulatory (HDAC6) microtubule components as detected by coimmunoprecipitation and mass spectrometric analyses of the mitotic SIRT4 interactome.Overexpression of SIRT4 resulted in a pronounced decrease of acetylated α-tubulin (K40) associated with altered microtubule dynamics in mitotic cells. SIRT4 or the N-terminally truncated variant SIRT4(ΔN28), which is unable to translocate into mitochondria, delayed mitotic progression and reduced cell proliferation. This study extends the functional roles of SIRT4 beyond mitochondrial metabolism, and suggests that SIRT4 acts as a novel centrosomal / microtubule-associated protein in the regulation of cell cycle progression. Thus, stress-induced SIRT4 may exert its role as tumor suppressor through mitochondrial as well as extramitochondrial functions, the latter associated with its localization at the mitotic spindle apparatus.

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Dual Tumor Suppressor and Tumor Promoter Action of Sirtuins in Determining Malignant Phenotype

Cited by 135 publications

References 170 publications

Lactate Increases Renal Cell Carcinoma Aggressiveness through Sirtuin 1-Dependent Epithelial Mesenchymal Transition Axis Regulation

Lactate Increases Renal Cell Carcinoma Aggressiveness through Sirtuin 1-Dependent Epithelial Mesenchymal Transition Axis Regulation

The Mitochondrial Protein VDAC1 at the Crossroads of Cancer Cell Metabolism: The Epigenetic Link

Subcellular localization and mitotic interactome analyses identify SIRT4 as a centrosomally localized and microtubule associated protein

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