Expression Profiling in Progressive Stages of Fumarate-Hydratase Deficiency: The Contribution of Metabolic Changes to Tumorigenesis

Ashrafian, Houman; O’Flaherty, Linda; Adam, Julie; Steeples, Violetta; Chung, Yuen Li; East, Philip; Vanharanta, Sakari; Lehtonen, Heli; Nye, Emma; Hatipoglu, Emine; Miranda, Melroy; Howarth, Kimberley; Shukla, Deepa; Troy, Helen; Griffiths, John R.; Spencer‐Dene, Bradley; Yusuf, Mohammed; Volpi, Emanuela V.; Maxwell, Patrick H.; Stamp, Gordon; Poulsom, Richard; Pugh, Christopher W.; Costa, Bárbara; Bardella, Chiara; Renzo, Maria Flavia Di; Kotlikoff, Michael I.; Launonen, Virpi; Aaltonen, Lauri A.; El‐Bahrawy, Mona; Tomlinson, Ian; Pollard, Patrick J.

doi:10.1158/0008-5472.can-10-1949

Cited by 63 publications

(50 citation statements)

References 51 publications

(66 reference statements)

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“…These results imply that decreased FH expression might contribute to tumorigenesis in RCC by promoting the expression of hypoxia-induced genes and cell proliferation, rather than by acting on aspects of the aggressive phenotype such as progression and invasion. In support of the present findings, Ashrafian et al [28] suggested that FH deficiency compels cells to adapt to an early, reversible, and progressive pro-tumorigenic metabolic environment characterized by the increased expression of HIF-1α target genes and glycolytic or biosynthetic gene expression changes. These authors concluded that these metabolic and gene expression changes seemed to be sufficient to promote cellular growth and proliferation, and subsequent expression changes putatively arising from genetic and epigenetic changes within preneoplastic cells might drive tumorigenesis.…”

Section: Discussionsupporting

confidence: 88%

Downregulation of Fumarate Hydratase Is Related to Tumorigenesis in Sporadic Renal Cell Cancer

Chihara

Yoon

et al. 2012

Urol Int

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Objective: Although germline mutations of fumarate hydratase(FH) are a useful molecular marker of hereditary leiomyomatosis and renal cell cancer (RCC) syndrome, their clinical significance in sporadic RCC has not been studied in detail. The aim of the present study was to investigate possible correlations between the expression of FH and the clinical implications of sporadic RCC. Materials and Methods:FH mRNA levels were evaluated in 140 tumor specimens from patients with primary RCC and in 62 specimens of corresponding normal-appearing kidney tissue using real-time quantitative polymerase chain reaction. Immunohistochemical staining was performed on 6 normal surrounding tissues and 71 RCC tissues. Results:FH mRNA levels were significantly lower in tumor tissues than in matched normal-appearing kidney tissues (p = 0.031). In all normal tissues, FH staining intensity was strong. However, the expression of FH showed no significant correlation with the pathological and clinical characteristics of patients with sporadic RCC. Conclusions: Our results showed that FH mRNA expression decreased significantly in correlation with the transition from normal renal parenchyma to RCC. FH may be an indicator or tumorigenesis in sporadic RCC and could be a potential target for therapies against RCC in the future.

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Section: Discussionsupporting

confidence: 88%

Downregulation of Fumarate Hydratase Is Related to Tumorigenesis in Sporadic Renal Cell Cancer

Chihara

Yoon

et al. 2012

Urol Int

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“…GSE26574 and GSE20896) (3,15). Concordant with our cell culture models, HLRCC tumors showed significantly increased expression levels of FTL, FTH1, and FOXM1 as well as the FOXM1 target genes AURKA, AURKB, and CDK1 compared to those in normal kidney tissues (Fig.…”

Section: Resultssupporting

confidence: 76%

Fumarate Mediates a Chronic Proliferative Signal in Fumarate Hydratase-Inactivated Cancer Cells by Increasing Transcription and Translation of Ferritin Genes

Kerins

Vashisht

Liang

et al. 2017

Molecular and Cellular Biology

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Germ line mutations of the gene encoding the tricarboxylic acid (TCA) cycle enzyme fumarate hydratase (FH) cause a hereditary cancer syndrome known as hereditary leiomyomatosis and renal cell cancer (HLRCC). HLRCC-associated tumors harbor biallelic FH inactivation that results in the accumulation of the TCA cycle metabolite fumarate. Although it is known that fumarate accumulation can alter cellular signaling, if and how fumarate confers a growth advantage remain unclear. Here we show that fumarate accumulation confers a chronic proliferative signal by disrupting cellular iron signaling. Specifically, fumarate covalently modifies cysteine residues on iron regulatory protein 2 (IRP2), rendering it unable to repress ferritin mRNA translation. Simultaneously, fumarate increases ferritin gene transcription by activating the NRF2 (nuclear factor [erythroid-derived 2]-like 2) transcription factor. In turn, increased ferritin protein levels promote the expression of the promitotic transcription factor FOXM1 (Forkhead box protein M1). Consistently, clinical HLRCC tissues showed increased expression levels of both FOXM1 and its proliferation-associated target genes. This finding demonstrates how FH inactivation can endow cells with a growth advantage.KEYWORDS ferritin, FH, FOXM1, fumarate, HLRCC, NRF2 H ereditary leiomyomatosis and renal cell cancer (HLRCC) patients carry a germ line-inactivating mutation in one of the fumarate hydratase (FH) alleles and are prone to developing skin leiomyomas, uterine fibroids, and renal cell carcinoma of type 2 papillary morphology (1). HLRCC-associated tumors harbor a loss of heterozygosity at the FH locus, indicating biallelic FH inactivation as the tumor-initiating event (1). However, it remains unclear how FH inactivation drives carcinogenesis.The most direct consequence of FH inactivation is intracellular fumarate accumulation. Accumulated fumarate can covalently modify cysteine residues of proteins in an uncatalyzed process termed succination and cause many alterations in cellular signaling (2). Succination in HLRCC cells was first discovered on Kelch-like ECH-associated protein 1 (KEAP1), a negative regulator of the nuclear factor (erythroid-derived 2)-like 2 (NRF2) transcription factor (3). Since HLRCC is driven by FH inactivation, chronic succination of KEAP1 results in constitutive NRF2 activation and increased expression of its target genes (3). Besides KEAP1, the Krebs cycle enzyme aconitase 2 (Aco2) was reported to be a succination target in Fh knockout mouse tissues, and succination inhibited its activity (2). Despite dramatic cellular changes induced by protein succina-

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“…This view is supported by the existing literature. For example, it was recently reported that mice exposed to 3 weeks of normobaric hypoxia had reduced complex II, complex IV, and aconitase activity in cardiac mitochondria 35 while fumarate accumulation leads to pseudohypoxic activation of hypoxiainducible factor-1α, 36 suggesting that many of the same reactions highlighted here indeed have important roles in hypoxic adaptation and, hence, survival. Our combined approach also yielded an unexpected benefit: Computational analysis was able to provide suggestions as to whether genes were under positive or negative selective pressure (an important distinction to which traditional genome-wide analytic techniques are blind).…”

Section: Downloaded Frommentioning

confidence: 77%

Genome-Scale Methods Converge on Key Mitochondrial Genes for the Survival of Human Cardiomyocytes in Hypoxia

Edwards

Sigurdsson

Robbins

et al. 2014

Circ Cardiovasc Genet

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Systems biology uses mathematical and computational methods to describe and explore complex biological networks. An important recent trend in systems biology has been the development and application of constraint-based modeling.1 Constraint-based modeling provides 3 significant advantages compared with traditional mathematical approaches for the study of large and complex biochemical systems. First, large models (up to thousands of reactions) can be accommodated. Thus, the entire metabolic network of a mitochondrion, for example, can be modeled. Second, precise descriptions of the behavior of each enzyme in the system (ie, rate laws) are not required. Finally, detailed information regarding the activity of a single protein (eg, whether an enzyme is allosterically modified or not) is not necessary. Thus, unlike traditional kinetic models, constraint-based models do not rely on, nor do they require, detailed knowledge of an enzyme's phosphorylation status, for example, nor the abundance of substrates and products. Clinical Perspective on p 415Constraint-based modeling is able to confer these advantages because the underlying models and assumptions are simple. The basic unit for constraint-based modeling is a network model, similar to the London Underground map. In the case of a biochemical network, this is constructed using (1) the known presence or absence of reactions based on genomic, proteomic, or biochemical data and (2) the known (speciesspecific) stoichiometry of all the chemical reactions included in the network. To this basic model are added a series of constraints (from which the method derives its name), including Background-Any reduction in myocardial oxygen delivery relative to its demands can impair cardiac contractile performance. Understanding the mitochondrial metabolic response to hypoxia is key to understanding ischemia tolerance in the myocardium. We used a novel combination of 2 genome-scale methods to study key processes underlying human myocardial hypoxia tolerance. In particular, we hypothesized that computational modeling and evolution would identify similar genes as critical to human myocardial hypoxia tolerance. Methods and Results-We analyzed a reconstruction of the cardiac mitochondrial metabolic network using constraintbased methods, under conditions of simulated hypoxia. We used flux balance analysis, random sampling, and principal component analysis to explore feasible steady-state solutions. Hypoxia blunted maximal ATP (−17%) and heme (−75%) synthesis and shrank the feasible solution space. Tricarboxylic acid and urea cycle fluxes were also reduced in hypoxia, but phospholipid synthesis was increased. Using mathematical optimization methods, we identified reactions that would be critical to hypoxia tolerance in the human heart. We used data regarding single-nucleotide polymorphism frequency and distribution in the genomes of Tibetans (whose ancestors have resided in persistent high-altitude hypoxia for several millennia). Six reactions were identified by both methods as being criti...

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Expression Profiling in Progressive Stages of Fumarate-Hydratase Deficiency: The Contribution of Metabolic Changes to Tumorigenesis

Cited by 63 publications

References 51 publications

Downregulation of Fumarate Hydratase Is Related to Tumorigenesis in Sporadic Renal Cell Cancer

Downregulation of Fumarate Hydratase Is Related to Tumorigenesis in Sporadic Renal Cell Cancer

Fumarate Mediates a Chronic Proliferative Signal in Fumarate Hydratase-Inactivated Cancer Cells by Increasing Transcription and Translation of Ferritin Genes

Genome-Scale Methods Converge on Key Mitochondrial Genes for the Survival of Human Cardiomyocytes in Hypoxia

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