iBet uBet web content aggregator. Adding the entire web to your favor.
iBet uBet web content aggregator. Adding the entire web to your favor.



Link to original content: https://pubmed.ncbi.nlm.nih.gov/31085323
Fumarate hydratase in cancer: A multifaceted tumour suppressor - PubMed Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2020 Feb:98:15-25.
doi: 10.1016/j.semcdb.2019.05.002. Epub 2019 May 22.

Fumarate hydratase in cancer: A multifaceted tumour suppressor

Christina Schmidt  1 , Marco Sciacovelli  2 , Christian Frezza  3
Affiliations
Review

Fumarate hydratase in cancer: A multifaceted tumour suppressor

Christina Schmidt et al. Semin Cell Dev Biol. 2020 Feb.

Abstract

Cancer is now considered a multifactorial disorder with different aetiologies and outcomes. Yet, all cancers share some common molecular features. Among these, the reprogramming of cellular metabolism has emerged as a key player in tumour initiation and progression. The finding that metabolic enzymes such as fumarate hydratase (FH), succinate dehydrogenase (SDH) and isocitrate dehydrogenase (IDH), when mutated, cause cancer suggested that metabolic dysregulation is not only a consequence of oncogenic transformation but that it can act as cancer driver. However, the mechanisms underpinning the link between metabolic dysregulation and cancer remain only partially understood. In this review we discuss the role of FH loss in tumorigenesis, focusing on the role of fumarate as a key activator of a variety of oncogenic cascades. We also discuss how these alterations are integrated and converge towards common biological processes. This review highlights the complexity of the signals elicited by FH loss, describes that fumarate can act as a bona fide oncogenic event, and provides a compelling hypothesis of the stepwise neoplastic progression after FH loss.

Keywords: Cancer; FH; Fumarate; Metabolism; Mitochondria.

PubMed Disclaimer

Conflict of interest statement

Competing interests

CF is member of the scientific advisory board of Owlstone Medicals, Cambridge, UK; and a scientific advisor for Istesso Limited, London, UK

Figures

Figure 1
Figure 1. Fumarate Hydratase and cancer.
A) schematic representation of Fumarate Hydratase (FH) gene and protein. B) Depiction of the chemical reaction catalysed by FH, which converts fumarate to malate. C) Representation of the various tissue where the sporadic or hereditary loss of FH leads to cancer. HLRCC: hereditary Leiomyomatosis and renal cell carcinoma.
Figure 2
Figure 2. Metabolic rewiring in FH-deficient cells.
The biallelic loss of FH leads to the truncation of the TCA cycle and the subsequent accumulation of fumarate (highlighted in orange). The combined disruption of the TCA cycle and the inhibition of Succinate Dehydrogenase (also known as Complex II of the respiratory chain) by fumarate significantly reduce mitochondrial respiration. To compensate for the loss of mitochondrial function, FH-deficient cells engage in a complex biochemical rewiring. First, FH-deficient cells shift towards aerobic glycolysis reducing the oxidation of glucose in the mitochondria (lilac arrows). Part of carbons from glucose are diverted toward the pentose phosphate pathway (PPP) to maintain redox homeostasis (lilac arrow). Furthermore, to maintain the remaining TCA cycle activity and sufficient NADH generation, FH-deficient cells increase glutamine oxidation (red arrows). Glutamine-derived carbons are further metabolized to fumarate and, via the haem pathway, to biliverdin and bilirubin, which is secreted in the medium, or are used to generate lipogenic acetyl-CoA via reductive carboxylation (yellow arrows). FH-deficient cells also activate multiple strategies to buffer the potentially toxic accumulation of fumarate. For instance, fumarate permeates the various intracellular compartments, including the nucleus, and can be released in the extracellular milieu. Fumarate accumulation leads to the aberrant production of argininosuccinate via the reversal of the urea cycle enzyme argininosuccinate lyase (ASL) (turquoise arrows). Of note, FH-deficient cells require constant supply of exogenous arginine to maintain this buffering system active and die when arginine is depleted. Finally, fumarate leads to the accumulation of adenylosuccinate, likely via the reversal of adenylosuccinate lyase (ADSL) within the purine nucleotide cycle (PNC). AMP= adenosine monophosphate; CI-V=Electron transport chain Complex I-V; PDH: pyruvate dehydrogenase; GLUT1=glucose transporter 1; HMOX1=haem oxygenase 1; IMP= inosine monophosphate.
Figure 3
Figure 3. Targets of succination in FH-deficient cells.
Fumarate, accumulated upon FH loss, leads to a post translational modification of cysteine residues of a variety of proteins (violet hexagons) called succination. The chemical reaction between fumarate and reactive thiol residues of proteins is in depicted in the insert. Succination of KEAP1 causes the stabilisation and activation of the NRF2-mediated anti-oxidant response. One of the targets of NRF2 is Haem Oxygenase 1 (HMOX1), which is required for the haem biosynthesis and degradation pathway, an essential pathway for the survival of FH-deficient cells. Succination of Iron Responsive Element Binding Protein 2 (IRP2) inhibits the repressive function of this protein on the translation of ferritin. The subsequent increase in ferritin causes a drop in free intracellular iron. In parallel, ferritin promotes the expression of Forkhead box protein M1 (FOXM1), a pro-mitotic protein that supports cell growth. Succination of the Fe-S cluster proteins Nfu1, Bola and Iscu impairs the Fe-S clusters assembly required by the electron transport chain complex I, contributing to defects in mitochondrial respiration. The reduction of iron and the succination of key cysteine residues in its catalytic core also inactivates the TCA cycle enzyme Aconitase 2 (ACO2). In the nucleus, the succination of SWI/SNF complex protein SMARCC1 inactivates this complex, affecting gene expression and chromatin remodelling. Finally, GSH succination causes the depletion of glutathione (GSH) stores, increasing oxidative stress, and triggering senescence in primary FH-deficient cells. CI-V=electron transport chain complex I-V; KEAP1=Kelch Like ECH Associated Protein 1; Bola1-3=BolA Family Member 1-3ISCU= Iron-Sulfur Cluster Assembly Enzyme; NFU1=NFU1 Iron-Sulfur Cluster Scaffold; NRF2=Nuclear Factor, Erythroid 2 Like 2; SMARCC1=SWI/SNF Related, Matrix Associated, Actin Dependent Regulator Of Chromatin Subfamily C Member 1. GCLC: glutamate-cysteine ligase; NQO1: NADH quinone oxidase 1.
Figure 4
Figure 4. Oncogenic signalling mediated via aKGDDs inhibition in FH-deficient cells.
Upon FH loss, fumarate accumulation inhibits the activity of various aKGDDs (grey hexagons). For instance, fumarate inhibits prolyl hydroxylases (PHDs), causing the stabilisation of the alpha subunit of a family of hypoxia inducible factors (HIFs) even in the presence of normal oxygen levels. The transcriptional response elicited by HIFs promotes angiogenesis, tumour growth, and aerobic glycolysis via increased expression of the glucose transporter GLUT1, and lactate dehydrogenase (LDHA). Furthermore, HIF triggers the expression of pyruvate dehydrogenase kinase 1 (PDK1), which phosphorylates and inhibits pyruvate dehydrogenase complex (PDH), a gatekeeper of glucose-derived pyruvate in the mitochondria. In the nucleus, fumarate accumulation induces a profound epigenetic reprogramming due to the inhibition of both DNA and histone demethylases (TETs and KDMs respectively). In particular, the inhibition of the demethylation of miR200 was shown to trigger an epithelial-to-mesenchymal transition (EMT) in FH-deficient cells. Finally, the inhibition of the RNA demethylase FTO by fumarate accumulation is predicted to increase RNA methylation. A=adenosine; FTO=Fat Mass and Obesity-Associated Protein; H3K4-me2= dimethylated arginine 4 in Histone H3; H3K4-3me= trimethylated H3K4; HIFα= hypoxia inducible factor subunit α; HIF-OH= hydroxylated; KDMs=Lysine Demethylases; miR200-C= unmethylated microRNA 200 gene; miR200-mC= methylated microRNA 200 gene; m6A=N6 methyl-adenosine; PDGF= Platelet Derived Growth Factor; TETs= Ten-Eleven Translocation Gene Proteins; VEGF=Vascular Endothelial Growth Factor.
Figure 5
Figure 5. Other molecular cascades affected by FH loss.
Upon FH loss, distinct signalling nodes have been found dysregulated (grey hexagons), and to activate key downstream proteins (green rectangles). For instance, the oxidation and inactivation of the protein phosphatase PTPN12 activates the kinase ABL1, which in turn activates mTOR and NRF2. The activation of mTOR is key to increase general protein synthesis via the phosphorylation of S6K. In parallel, AMPK is suppressed in FH-deficient cells, further activating mTOR and Acetyl CoA carboxylase (ACC), thus promoting lipid biosynthesis. The inactivation of AMPK also leads to the p53-dependent suppression of the iron transporter DMT1, decreasing iron uptake and reducing of the free iron pool. FH deficient cells were shown to depend on the activity of a set of Adenylate Cyclases (AC), which increase the total pool of cyclic AMP (cAMP) in the cells. Finally, the accumulation of fumarate increases resistance to DNA damage by ionising radiations (IR) and favours non-homologous end-joining upon DNA damage, via inhibition of KDM6, a key histone demethylase implicated in chromatin unfolding for DNA repair. ABL1= Abelson murine leukaemia viral oncogene homolog 1; DMT1= Divalent metal transporter 1; H3K36-me2= dimethylated arginine 36 on Histone H3; H3K36-3me= trimethylated H3K36; KDMs=Lysine Demethylases; mTOR= mechanistic target of rapamycin; p53= tumour suppressor protein 53; AMPK= AMP-activated protein kinase; PTPN12=Tyrosine-protein phosphatase non-receptor type 12; S6K= S6 ribosomal protein kinase.
Figure 6
Figure 6. Tumorigenesis in FH-deficient cancer.
We hypothesise that tumorigenesis in FH-deficient cells is a multi-step process. First, upon FH loss, cells undergo a series of biochemical adaptations in order to compensate for the loss of FH and for the truncation of the TCA cycle. These compensatory changes support the elevation of intracellular fumarate, which in turn can lead to senescence due, at least in part, to oxidative stress. In parallel, fumarate can induce epigenetic changes, such as hypermethylation of p16, that can enable the bypass of senescence. The activation of additional oncogenic cascades, including those orchestrated by NRF2, ABL1, and HIF contribute to cellular transformation.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Hanahan D, Weinberg RA. The Hallmarks of Cancer. Cell. 2000;100:57–70. doi: 10.1016/S0092-8674(00)81683-9. - DOI - PubMed
    1. Hanahan D, Weinberg RA. Hallmarks of Cancer: The Next Generation. Cell. 2011;144:646–674. doi: 10.1016/j.cell.2011.02.013. - DOI - PubMed
    1. Freund E. Zur Diagnose des Carcinoms. Wiener Medizinische Blätter. 1885;9:268–269. https://www.nytimes.com/1887/12/24/archives/sugar-and-cancer.html.
    1. Wassermann M, Keysser AV, Wassermann F. Beiträge zum problem: Geschwülste von der blutbahn aus therapeutisch zu beeinflussen. Dtsch Medizinische Wochenzeitschrift. 1911;37:2389–2391.
    1. Van Alstyne EV, Beebe SP. Diet Studies in transplantable Tumors : I. The Effect of non-carbohydrate Diet upon the Growth of transplantable Sarcoma in Rats. J Med Res. 1913;29:217–232. - PMC - PubMed

Publication types

Substances

LinkOut - more resources