Fumarate hydratase in cancer: A multifaceted tumour suppressor. (February 2020)

• Record Type: Journal Article
• Authors: Schmidt, Christina; Sciacovelli, Marco; Frezza, Christian
• Is Part Of: Seminars in cell & developmental biology. Volume 98(2020)
• Page Start: 15
• Page End: 25
• Publication Date: 2020-02
• Subjects: A Adenosine -- ABL-1 Abelson murine leukaemia viral oncogene homolog 1 -- AC Adenylate Cyclases -- ACC Acetyl CoA carboxylase -- ACO Aconitase -- ADSL Adenylosuccinate lyase -- AMP adenosine monophosphate -- AMPK AMP-activated protein kinase -- ASL argininosuccinate lyase -- BOLA BolA family member -- cAMP cyclic AMP -- CDKN2A cyclin dependent kinase inhibitor 2A -- CI-V Electron transport chain Complex I-V -- DMT1 divalent metal transporter 1 -- DDR DNA-damage response -- FOXM1 forkhead box protein M1 -- FH Fumarate hydratase -- FTO fat mass and obesity associated -- GCLC glutamate-cysteine ligase catalytic subunit -- GLUT1 glucose transporter 1 -- GSH glutathione -- H3K4-me2 dimethylated histone H3 at lysine 4 -- H3K4-3me trimethylated histone H3 at lysine 4 -- H3K36-me2 dimethylated histone H3 at lysine 36 -- H3K36-3me trimethylated histone H3 at lysine 63 -- HIFα hypoxia-inducible factor subunit α -- HIF−OH hydroxylated hypoxia-inducible factor -- HIFs hypoxia -inducible factors -- HLRCC Hereditary Leiomyomatosis and Renal Cell Cancer -- HMOX haem oxygenase 1 -- IDH isocitrate dehydrogenase -- IMP inosine monophosphate -- IR ionising radiations -- IRP2 iron regulatory protein 2 -- ISCU Fe-S cluster assembly enzyme -- JmjC-KDMs Jumonji-containg histone lysine demethylases -- KDMs Lysine demethylases -- KEAP1 Kelch-like ECH-associated protein1 -- αKG α-ketoglutarate -- aKGDDs αKG-dependent-dioxygenases -- LDH-A lactate dehydrogenase A -- miR200-C unmethylated microRNA 200 gene -- miR200-mC methylated microRNA 200 gene -- m6A N6 methyl-adenosine -- mTORC1 mTOR complex1 -- NFU1 Fe-S cluster scaffold -- NQO1 NAD(P)H dehydrogenase quinone 1 -- NRF2 Nuclear Factor, Erythroid 2 Like 2 -- p53 tumour suppressor protein 53 -- PARP poly-ADP ribose polymerase inhibitors -- PDGF platelet derived growth factor -- PDH pyruvate dehydrogenase -- PDKs pyruvate dehydrogenase kinases -- PHDs prolyl-hydroxylases -- PNC purine nucleotide cycle -- PPP pentose phosphate pathway -- pro-NEHJ pro-non homologous end joining -- PTPN12 protein-tyrosine phosphatase N12 -- RCC renal cell carcinomas -- SNAI2 Snail homolog 2 -- 2SC S-2-succino) cysteine -- SDH succinate dehydrogenase -- S6K S6 ribosomal protein Kinase -- SMARCC1 SWI/SNF Related, Matrix Associated, Actin Dependent Regulator Of Chromatin Subfamily C Member 1 -- SNF5 SWI/SNF Related, Matrix Associated, Actin Dependent Regulator Of Chromatin, Subfamily B, Member 5 -- TETs Ten-Eleven Translocation -- TCA Tricarboxylic acid -- Tsc1/2 Tuberous Sclerosis complex1/2 -- VEGF vascular endothelial growth factor -- ZEB Zinc Finger E-Box Binding Homeobox; FH -- Mitochondria -- Fumarate -- Cancer -- Metabolism; Cytology -- Periodicals; Developmental biology -- Periodicals; 571.6
• DOI: 10.1016/j.semcdb.2019.05.002
• Languages: English
• ISSNs: 1084-9521

Abstract

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.