Review
Fumarate hydratase in cancer: A multifaceted tumour suppressor

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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.

Introduction

Oncogenesis is a multistep process during which cells acquire molecular features known as “Hallmarks of Cancer”, which pave the way to malignant transformation [1]. The reprogramming of cellular metabolism is now widely considered a pivotal hallmark of cancer that allows cancer cells to survive, proliferate, and metastasize [2]. Although added to the list of the hallmarks only recently [2], the first piece of evidence that cellular metabolism is reprogrammed in cancer was provided already in 1887 by Ernst Freund, a Viennese physician, who observed high sugar levels in the blood of cancer patients [3]. Based on this observation he proposed that reducing the amount of sugar could impact the tumour growth [3]. In 1911 the German scientist Wassermann postulated that accelerated proliferation of cancer cells was associated with an increased oxygen consumption [4]. To validate this hypothesis, he tried, without success though, to target tumours using inhibitors of respiration such as selenium derivates [4]. Just two years later, in 1913, Eleanor Van Ness Van Alstyne and colleagues showed that increased carbohydrate intake resulted in accelerated rat sarcoma growth [5], which was further confirmed by William Woglom in 1915 [6]. These works supported the notion that tumours use nutrients such as glucose and oxygen in a different way than normal tissue. A few years later, these findings were systematically investigated by Otto Warburg. He demonstrated that cancer cells ferment most of their glucose to lactate even in the presence of normal levels of oxygen when glucose should be fully oxidised to carbon dioxide through cellular respiration [7]. After the discovery that respiration is carried out by the mitochondria, Warburg concluded that all cancers must originate from a mitochondrial dysfunction [8].

After Warburg’s discoveries, the field of cancer metabolism was neglected until the beginning of the 21st century, when major discoveries and technical advances, including the advent of metabolomics, rekindled the field. Furthermore, thanks to the availability of large collections of gene expression data from cancer patients, the metabolic landscape of cancer could be extensively assessed using gene expression of metabolic enzymes. These bioinformatics analyses showed that both nuclear and mitochondrial DNA-encoded mitochondrial genes are suppressed in cancer [[9], [10], [11]] and this feature is associated with poor clinical outcome and metastasis [9]. Noteworthy, not all tumours exhibit mitochondrial impairment and it should be highlighted that the complete loss of mitochondrial function can be detrimental for cancer cells [12,13]. The role of mitochondrial dysfunction in cancer was further corroborated by recent sequencing efforts that led to the discovery that mitochondrial genes, including fumarate hydratase (FH), succinate dehydrogenase (SDH) and isocitrate dehydrogenase (IDH), when mutated, cause hereditary and sporadic forms of cancer (reviewed in [14]). Although these discoveries were made almost twenty years ago, the mechanisms underpinning transformation in these metabolically impaired tumours are still under intense investigation and could provide unique mechanistic insights into the link between dysregulated mitochondrial function and transformation. In this review, we will focus on the role of FH loss in cancerous transformation.

Section snippets

Fumarate Hydratase mutations in human diseases

In the human genome the gene encoding FH is located in the chromosome locus 1p43 and encompasses 22229 bases transcribing for 10 exons (NCBI database, NG_012338.1) that give rise to the FH monomer, which exhibits a “tridomain” structure, with a central domain involved in the interactions with the other monomers, an N-terminal Lyase 1 domain, and a C-terminal Fumarase C domain (Ensembl database, FH-001 ENST00000366560.3) (Fig. 1A). Interestingly, the FH gene encodes for both the cytosolic and

Metabolic rewiring in FH-deficient cells

The TCA cycle is a set of metabolic reactions within the mitochondria that represents the final converging route for the oxidation of lipids, carbohydrates, and amino acids [33]. Consequently, TCA cycle enzymes are essential for cell growth and survival, and it came as a surprise that FH loss could not only be tolerated by cells but that it could also cause cancer. Therefore, it was argued that FH-deficient cells must respond to this mitochondrial impairment by compensatory metabolic changes.

A possible paradigm of tumorigenesis in HLRCC

In the previous paragraphs of this review, we provided compelling evidence that upon FH loss cells orchestrate a multifaceted reprogramming that includes pro-survival metabolic adaptations and the activation of oncogenic cascades. However, the specific contribution of these signalling cascades towards cellular transformation is not fully understood. Based on our current understanding, we postulate that tumorigenesis driven by FH loss occurs via a series of steps over time, largely divided into

Competing interests

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

Authors’ contribution

CS, MS, and CF jointly wrote the manuscript.

Authors’ information and funding

CS is a PhD student and MS is a Research Associate in the laboratory of CF. CF is a group leader at the MRC Cancer Unit, University of Cambridge. MS and CF are funded by an MRC Core Funding to the MRC Cancer Unit MRC_MC_UU_12022/6; CS is funded by the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No 722605.

Acknowledegment

We thank all the members of the Frezza’s laboratory for insightful discussion.

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