Review article
Oncometabolites: Unconventional triggers of oncogenic signalling
cascades
Marco Sciacovelli, Christian Frezza n
Medical Research Council Cancer Unit, University of Cambridge, Hutchison/MRC Research Centre, Box 197, Cambridge Biomedical Campus,
Cambridge CB2 0XZ, United Kingdom
article info
Article history:
Received 31 January 2016
Received in revised form
11 April 2016
Accepted 19 April 2016
Available online 23 April 2016
Keywords:
Mitochondria
Cancer
Oncometabolites
FH
SDH
IDH
Fumarate
Succinate
2-Hydroxyglutarate
abstract
Cancer is a complex and heterogeneous disease thought to be caused by multiple genetic lesions. The
recent finding that enzymes of the tricarboxylic acid (TCA) cycle are mutated in cancer rekindled the
hypothesis that altered metabolism might also have a role in cellular transformation. Attempts to link
mitochondrial dysfunction to cancer uncovered the unexpected role of small molecule metabolites, now
known as oncometabolites, in tumorigenesis. In this review, we describe how oncometabolites can
contribute to tumorigenesis. We propose that lesions of oncogenes and tumour suppressors are only one
of the possible routes to tumorigenesis, which include accumulation of oncometabolites triggered by
environmental cues.
& 2016 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY license
(http://creativecommons.org/licenses/by/4.0/).
1. Background
Cancer is a complex and multifactorial disease. Although its
malignant features have been known for centuries, it was not until
the advent of modern biology that the molecular determinants of
cancer transformation have been elucidated. In 1911, pioneering
work from Peyton Rous showed that avian sarcomas were transmissible
to other healthy fowls through a filtrate of the tumours
devoid of cells [1,2]. Later on, the agent present in those extracts
and responsible for tumour formation was identified as a retrovirus,
later called Rous Sarcoma Virus. This important discovery
started the field of tumour virology and led to the identification of
the oncogene v-Src [3–6], first in retroviruses and then in normal
avian DNA [7]. The emerging idea was that cancer was caused by
alterations of the genome. Since then, other oncogenes, including
MYC, RAS, ERBB, PI3K [2,6] and the first tumour suppressor gene
RB1 [8,9] were discovered. The causative role of RB1 inactivation in
retinoblastoma formation reinforced the concept of cancer initiation
driven by genomic alterations. These discoveries led Knudson
and colleagues to hypothesise a “multiple-hit” model of tumorigenesis,
where multiple genetic alterations are required to
achieve full blown transformation [8]. We now know that tumorigenesis
requires the acquisition of multiple enabling features,
the hallmarks of cancer, among which metabolic rewiring is becoming
increasingly recognised [10,11]. In a seminal paper, Shim
et al. showed that Lactate Dehydrogenase A (LDHA) is a target of
the proto-oncogene MYC and is required for MYC-induced anchorage-independent
growth in both human and mouse cellular
models [12]. Since then, scientists have uncovered several aspects
of the metabolic reprogramming of cancer, and realised that not
only dysregulated metabolism is required to sustain proliferation
but it also affects tumour microenvironment and the immune
response [11].
The discovery that mutations in the metabolic genes Fumarate
hydratase (FH) [13], Succinate dehydrogenase (SDH) [14–17], and
Isocitrate dehydrogenase (IDH) [18–21] lead to cancer further
supported a primary role of metabolic alterations in tumorigenesis.
Thanks to these discoveries, a novel paradigm is emerging
whereby mitochondrial metabolites that accumulate in these
conditions act as oncogenic signalling molecules, becoming bona
fide oncometabolites. Recent data suggest that reprogramming of
cellular metabolism occurs both as direct and indirect consequence
of oncogenic mutations and that environmental cues,
such as hypoxia, could affect the metabolic phenotype of cancer
cells and the abundance of oncometabolites, amplifying oncogenic
cascades. In this review we describe the main oncogenic functions
Contents lists available at ScienceDirect
journal homepage: www.elsevier.com/locate/freeradbiomed
Free Radical Biology and Medicine
http://dx.doi.org/10.1016/j.freeradbiomed.2016.04.025
0891-5849/& 2016 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
n Corresponding author.
E-mail address: cf366@MRC-CU.cam.ac.uk (C. Frezza).
Free Radical Biology and Medicine 100 (2016) 175–181
of oncometabolites and how their abundance can be affected by
genetic mutations and environmental cues.
2. TCA cycle enzymes mutations and the emerging paradigm
of oncometabolite-driven tumorigenesis
SDH was the first mitochondrial enzyme found mutated in
cancer [14]. It was the first time that mutations of a mitochondrial
enzyme, once thought to be incompatible with life [22], were
linked to tumour predisposition. This and the subsequent discovery
of FH mutations in renal cancer catalysed a substantial
effort to elucidate the molecular links between mitochondrial
dysfunction and tumorigenesis. These major findings are reported
below.
2.1. Succinate dehydrogenase (SDH)
SDH is an enzyme of the TCA cycle involved in the conversion
of succinate to fumarate and a key component of the mitochondrial
respiratory chain. This enzyme is composed of four subunits,
SDHA, SDHB, SDHC, SDHD; and two assembly factors, SDHF1 and
SDHF2 [23]. Mutations in SDH are found in familial paraganglioma
and pheochromocytoma [14–17,24,25], renal carcinomas [26],
T-Cell leukaemia [27], and gastrointestinal stromal tumours [28].
SDH deficiency causes profound metabolic changes. Recent work
showed that mouse SDH-deficient cells have a high demand of
extracellular pyruvate and utilise glucose-derived carbons for aspartate
biosynthesis through pyruvate carboxylation [29,30]. Interestingly,
this metabolic rewiring could be used to selectively
target Sdhb-/- cells [29].
One of the most striking features of SDH-deficient cells is the
accumulation of succinate [31], a metabolite implicated in tumorigenesis
and, for this reasons, recently defined an oncometabolite
[32]. Among its many functions, succinate is a competitive
inhibitor of α-ketoglutarate (aKG)-dependent dioxygenases
(aKGDD), a class of enzymes involved in a plethora of biological
processes. For instance, succinate inhibits prolyl-hydroxylases
(PHDs), aKGDDs involved in the degradation of Hypoxia Inducible
Factor (HIF), leading to the aberrant stabilisation of HIFs even
when oxygen is abundant, a condition called pseudohypoxia [33].
Succinate inhibits other aKGDDs, including Ten-Eleven Translocation
proteins (TETs), enzymes involved in DNA demethylation
[34,35], leading to CpG island hypermethylation [36]. Succinate
also causes the inhibition of Histone Lysine Demethylases (KDMs),
aKGDDs involved in histone demethylation [34], causing even
further epigenetic changes [36,37]. Interestingly, DNA hypermethylation
phenotype was associated with dedifferentiation
and increased invasion potential of SDH-deficient tumours [36,38].
However, the molecular mechanisms behind this phenotypic
switch are still under investigation.
2.2. Fumarate hydratase
FH is an enzyme of the TCA cycle that converts fumarate to
malate. Whilst homozygous FH mutations cause fumaric aciduria,
a condition associated with infantile encephalopathy and brain
malformations [39], heterozygous FH mutations followed by the
loss of heterozygosity of the second allele cause Hereditary Leiomyomatosis
and Renal Cell Cancer (HLRCC) [13,40]. FH is also
mutated in paraganglioma, pheochromocytoma [41,42], downregulated
in sporadic clear cell carcinomas [43] and deleted in
neuroblastoma [44]. Cristal structure of human FH showed that
clinically-relevant mutations affect evolutionary conserved regions
involved in either the catalytic activity or the folding and stability
of the protein [45], leading to abnormal accumulation of fumarate
[46–48]. Loss of FH also leads to a complex rewiring of cell metabolism.
For instance, FH loss leads to an increased uptake of
glutamine that is diverted into haem synthesis and bilirubin excretion
to maintain mitochondrial NADH production and mitochondrial
potential. Also, the accumulation of fumarate in FHdeficient
cells leads to the reversal of the urea cycle enzyme argininosuccinate
lyase (ASL), causing the production of argininosuccinate
from fumarate and arginine [47,48]. This metabolic rewiring
makes FH-deficient cells auxotrophic for arginine and
sensitive to arginine-depriving agents such as arginine deiminase
[48]. Interestingly, arginine depletion has been proposed as therapeutic
intervention for renal cell carcinoma [49]. However, in this
case, arginine auxotrophy is caused by inactivation of argininosuccinate
synthase (ASS1), the urea cycle enzyme that converts
aspartate and citrulline to argininosuccinate, which is then converted
to arginine and fumarate by ASL. Inactivation of ASS1 has
been shown to allow the diversion of aspartate from the urea cycle
to pyrimidine biosynthesis, favouring tumour growth [50]. It is
tempting to speculate that in FH-deficient cells the activity of ASS1
is inhibited by the accumulation of argininosuccinate, leading to
increased pyrimidine biosynthesis. Consistent with an increased
utilisation of aspartate, the intracellular levels of this metabolite
are very low in FH-deficient cells [48]. However, the rate of pyrimidine
synthesis is these cells has not been assessed yet.
Fumarate has been implicated in tumorigenesis of HLRCC and,
for this reason, included in the list of oncometabolites [51]. Similarly
to succinate, fumarate inhibits several aKGDDs, including
PHDs, leading to pseudohypoxia [52]. Of note, the non-canonical
activation of NF-kB signalling by fumarate also contributes to the
pseudohypoxic phenotype in FH-deficient cells [53]. Although
pseudohypoxia has been considered an important driver of tumorigenesis,
recent data showed that HIFs are dispensable for the
formation of benign pre-tumorigenic lesions in Fh1-deficient mice
[54]. Therefore, other mechanisms have been proposed to explain
fumarate-dependent tumorigenesis. For instance, recent findings
identified the Abelson murine leukemia viral oncogene homolog 1
(ABL-1) as potential driver in fumarate-dependent tumorigenesis
[55]. Interestingly, ABL-1 inhibitors suppress the invasion properties
of FH-deficient cells both in vitro and in vivo. Mechanistically,
through ABL-1 activation, fumarate stimulates an antioxidant response
mediated by transcription factor NFE2-related factor 2
(NRF2), and a metabolic rewiring through activation of mammalian
target of rapamycin (mTOR)-HIF axis [55]. Fumarate was also
shown to promote broad epigenetic changes [56], caused by inhibition
of histone and DNA demethylases [34,35]. However, the
relevance of these epigenetic changes in tumorigenesis is still
under investigation. Finally, fumarate, a mild electrophilic molecule,
was demonstrated to react with thiol residues of proteins
through a process called succination [57–60]. This post-translational
modification is a distinctive feature of FH-deficient tumours
and now used for diagnostic purposes [58]. Although several
succinated proteins have been identified in FH-deficient cells
[60,61], the biological roles of this process are still under investigation.
It was recently reported that succination of mitochondrial
Aconitase (ACO2) impairs its enzymatic activity [61]
and succination of Kelch-Like ECH-associated protein-1 (KEAP-1)
inhibits its negative modulatory effect on the transcription factor
NRF2 [54,62]. Although NRF2 activation has been previously reported
as pro-tumorigenic event [63], its role in FH-deficient tumours
is still debated. The thiol residue of the antioxidant tripeptide
Glutathione (GSH) is also subject of succination [64,65]
and its depletion causes oxidative stress, which induces senescence
in primary FH-deficient kidney cells. Of note, genetic ablation
of p21, a major player in senescence induction, induces
transformation of benign cysts in FH-deficient mice indicating the
tumour-suppressive role of senescence in FH-mediated
176 M. Sciacovelli, C. Frezza / Free Radical Biology and Medicine 100 (2016) 175–181
tumorigenesis [65]. Besides revealing potential mechanisms of
tumorigenesis caused by loss of FH, these works led to the identification
of fumarate as important regulator of redox homeostasis,
which goes beyond FH deficiency. For instance, Jin et al. showed
that fumarate generated within the TCA cycle can regulate the
activity of the antioxidant protein Glutathione Peroxidase (GPx),
modulating the antioxidant capacity of the cell. Of note, this
function of fumarate is not caused by succination but, rather, by
the binding of fumarate to the protein [66].
2.3. Isocitrate dehydrogenase (IDH1/IDH2)
Isocitrate dehydrogenases (IDHs) are homodimeric enzymes
responsible for the reversible oxidative decarboxylation of isocitrate
to aKG. Three different isoforms of IDH have been described,
which have distinct subcellular compartmentalisation.
IDH3 is a NADþ-dependent mitochondrial enzyme, core component
of the TCA cycle. The other two IDH isoforms (IDH1 and
IDH2) are NADPþ-dependent proteins expressed respectively in
cytosol and mitochondria [25,67]. Heterozygous missense mutations
affecting IDH1 and IDH2 were found in gliomas [18,19] and in
acute myeloid leukaemia (AML) [20,21]. At odds with SDH and FH,
IDH mutations are gain-of-function mutations and confer to the
enzyme the ability to produce the oncometabolite D-2-hydroxyglutarate
(D-2HG) [68,69]. 2HG, the reduced form of aKG, is
naturally present in two optic isomers,D-2HG and L-2HG. In normal
cells, 2HG is a minor by-product of metabolism and its levels
are kept low by the activity of a conserved family of proteins, the
L/D-2-hydroxyglutarate dehydrogenases (L2HGDH and D2HGDH)
[70,71], which convert 2HG to aKG. Homozygous germline mutations
in these two enzymes are responsible for a severe form of
2HG aciduria characterised by developmental abnormalities and
premature death in children [71,72]. Moreover, mutations in
L2HGDH have been associated with brain tumours [73] and, recently,
with kidney cancer [74]. Both isomers of 2HG can affect the
enzymatic activity of aKGDD. Whilst the role of D-2HG in PHD
inhibition and HIF stabilisation is still controversial [75], this
metabolite was shown to inhibit both TETs and KDMs [76,77].
Consistently, IDH1-mutant tumours exhibit DNA hypermethylation
in gliomas [78] and leukemia [79], and histone hypermethylation
[80]. Evidence that TET2 and IDH1/2 mutations are mutually exclusive
in AML tumours [79] supports the notion that TETs inhibition
and the ensuing DNA hypermethylation are instrumental
to IDH-driven tumorigenesis. This hypothesis has been recently
corroborated by the finding that DNA hypermethylation causes
reduced CCCTC-binding factor (CTCF) binding to DNA, leading to
aberrant activation of the oncogene Platelet-derived growth factor
receptor (PDGFRA) [81] in gliomas. Other mechanisms have been
proposed to contribute to 2HG-dependent tumorigenesis in IDHmutant
tumours. For instance, 2HG accumulation inhibits ATP
Synthase within the mitochondria activating a series of downstream
signals that involve mTOR suppression [82]. Regardless the
molecular underpinnings, research on IDH-mutant tumours uncovered
an unexpected but powerful role of 2HG as oncogenic
molecule. In support of this role, it was demonstrated that the
incubation of cells with D-2HG promotes cytokine independence
and alters differentiation in hematopoietic cells, proving compelling
evidence that a small molecule is sufficient to transform cells
[83]. Interestingly, the role of 2HG in tumorigenesis goes beyond
IDH-mutant tumours. For instance, 2HG accumulation can be
driven by a metabolic reprogramming caused by MYC activation in
aggressive breast cancer, leading to DNA hypermethylation akin to
that observed in IDH mutant tumours [84]. Also, 2HG can be
produced by the promiscuous activity of the enzyme Phosphoglycerate
Dehydrogenase, another important oncogene in
breast cancer [85].
3. Succinate, fumarate, and 2HG: overlapping and distinct
functions
The brief description above suggests that signalling cascades
elicited by fumarate, succinate, and 2HG, share some common
targets but also exhibit distinct features, which can explain the
Fig. 1. Schematic representation of overlapping features of tumours harbouring FH, SDH, and IDH mutations. Mutations in FH, SDH, and IDH lead to the accumulation of fumarate,
succinate, and 2HG, respectively, activating a plethora of signalling cascades. Converging signatures, mainly mediated by aKGDD inhibition, include pseudohypoxia, histone and
DNA hypermethylation. The colour of text indicates metabolic alterations (red), epigenetic alterations (blue), post-translational modifications (green) and other pro-tumorigenic
alterations (black) elicited by these metabolites. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)
M. Sciacovelli, C. Frezza / Free Radical Biology and Medicine 100 (2016) 175–181 177
different types of tumours associated with their accumulation
(Fig. 1). The converging signatures, mostly mediated by aKGDD
inhibition, include pseudohypoxia and broad epigenetic changes,
such as DNA and histones hypermethylation. Interestingly, recent
studies showed that pseudohypoxic genes, besides being regulated
by HIFs, are also transcriptionally controlled by TETs. Therefore,
epigenetic changes are required for a full pseudohypoxic response
triggered by these metabolites. However, these metabolites have
different IC50 for TETs and KDMs [35], suggesting that their epigenetic
effect might have different outcomes, with fumarate being
the most effective TETs inhibitor and 2HG the poorest. These
metabolites exert other distinct biological functions. As indicated
above, fumarate accumulation leads to protein succination, triggering
a plethora of biological changes that may synergise with or
counteract aKGDDs inhibition. Also, accumulation of 2HG has been
shown to increase protein succinylation via inhibition of SDH and
subsequent accumulation of succinyl-CoA [86]. This post translation
modification leads to a reprogramming of mitochondrial
function and induces resistance to apoptosis. Finally, fumarate and
2HG elicit opposite effects on mTOR signalling, with important
consequences for the development of specific tumour types
[55,82]. Therefore, although characterised by a very similar chemical
structure, succinate, fumarate, and 2HG, appear to have
distinct biological roles, well beyond inhibition of aKGDDs.
4. Environmental cues regulates oncometabolite production
The observation that 2HG is sufficient to promote tumorigenesis
[83] raised the possibility that environmental cues that increase
this metabolite could contribute to tumorigenesis, without
underpinning IDH mutations. In support to this hypothesis, it has
been shown that hypoxia leads to the production of 2HG (Fig. 2),
either via reductive carboxylation [87] or via promiscuous substrate
usage of LDHA [88] and Malic Dehydrogenase 1/2 [89]. Since
hypoxia is a common feature of solid tumours [90] it is possible
that hypoxia-driven production of 2HG elicits (epi)genetic changes
that drive or amplify the process of tumorigenesis.
2-HG is not the only oncometabolite whose levels are altered
by hypoxia. During ischemia, succinate significantly accumulates
in multiple organs and its oxidation is responsible for ROS
generation during reperfusion [91]. Succinate was also shown to
increase under hypoxic conditions, in cancer cells cultured in 3D
scaffolds [92], consistent with its role as hypoxia sensing molecule.
Other cues trigger oncometabolite accumulation. For instance,
fumarate was shown to accumulate in hyperglycemic conditions
[59,93] (Fig. 2), likely as a consequence of mitochondrial dysfunction
caused by glucose accumulation [94,95]. We hypothesise
that fumarate accumulation observed in diabetes [93,95], could, at
least in part, explain the increase cancer risk in these patients.
Together, these studies seem to suggest that environmental or
nutritional cues may cause dysregulation of mitochondrial function,
leading to oncometabolite accumulation in the absence of
underpinning oncogenic mutations.
5. Future perspectives
Oncometabolites are emerging as key components of the communication
between mitochondria and the nucleus. Chronic accumulation
of these small molecules triggered by genetic or environmental
cues may alter the epigenetic landscape of the cell eliciting
oncogenic signalling cascades. This new paradigm of tumorigenesis
challenges the role of gene mutations as the exclusive driving mechanism
of tumorigenesis and suggests that the latter may be only
one of the possible mechanisms that lead to transformation.
Competing interests
The authors declare no competing interests.
Authors’ contribution
MS and CF jointly wrote the manuscript.
Authors’ information
MS is a Research Associate in the laboratory of CF. CF is a group
leader at the MRC Cancer Unit, University of Cambridge,
Fig. 2. An oncometabolic perspective of tumorigenesis. Schematic representation of how oncometabolite affect the process of tumorigenesis. The indicated oncometabolites
can accumulate as a consequence of mutations of TCA cycle enzymes or environmental cues, such as hypoxia or hyperglycemia. These metabolites can act as proper
oncogenic triggers and can drive transformation even in the absence of genetic alterations.
178 M. Sciacovelli, C. Frezza / Free Radical Biology and Medicine 100 (2016) 175–181
Cambridge, UK. MS and CF are funded by an MRC Core Funding to
the MRC Cancer Unit.
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