The enigmatic MYC oncogene, which participates broadly in cancers, revealed itself recently as the maestro of an unfolding symphony of cell growth,
proliferation, death, and metabolism. The study of MYC is arguably most challenging to its students but at the same time exhilarating when MYC
reveals its deeply held secrets. It is the excitement of our richer understanding of MYC that is captured in each review of this special issue of Genes &
Cancer. Collectively, our deeper understanding of MYC reveals that it is a symphony conductor, controlling a large orchestra of target genes. Although
MYC controls many orchestra sections, which are necessary but not sufficient for Myc function, ribosome biogenesis stands out to reveal Myc’s
primordial function particularly in fruit flies. Because ribosome biogenesis and the associated translational machinery are bioenergetically demanding,
Myc’s other target genes involved in energy metabolism must be coupled with energy demand to ensure that cells can replicate their genome and
produce daughter cells. Normal cells have feedback loops that diminish MYC expression when nutrients are scarce. On the other hand, when
deregulated Myc transforms cells, their constitutive bioenergetic demand can trigger cell death when energy is unavailable. This special issue captures
the unfolding symphony of MYC-mediated tumorigenesis through reviews that span from a timeline of MYC research, fundamental understanding of
how the MYC gene itself is regulated, the study of Myc in model organisms, Myc function, and target genes to translational research in search of new
therapeutic modalities for the treatment of cancer.
Keywords: oncogene, transcription, cancer, targeted therapy
standing of this gene is essential for the
prevention and combat of these devastat-
ing diseases. MYC is a prototypical
oncogene that has a rich and circuitous
history (Wasylishen & Penn,1 this issue)
with surprises lurking around every cor-
ner along the journey, leading to our cur-
rent understanding of this enigmatic
gene and its product c-Myc (hereafter
termed Myc).2 In our collective quest to
understand the MYC gene, which plays a
broad role in cell growth and prolifera-
tion in normal, cancer, and stem cells, we
need to consider how a cell is made and
how MYC influences this process. A cell
comprises 55% protein, 25% RNA, 10%
lipid, and about 3% DNA, with half of
the RNA and protein consisting of ribo-
somal RNA and proteins. In fact, 50% of
ongoing RNA synthesis involves the pro-
duction of rRNAs. Hence, the making
of a cell is largely determined by its abil-
ity to undergo ribosome biogenesis,
which imposes a significant bioenergetic
he MYC oncogene contributes pro-
foundly to human cancer morbidity
and mortality, and hence the under-
demand on the cell.3,4 As the cell grows
in the G1 phase of the cell cycle, energy
and anabolic building blocks must be
concurrently imported to meet the meta-
bolic demand in preparation for crossing
the start point and entry into S phase.
Upon completion of DNA synthesis that
is coupled with surveillance for replica-
tion fidelity, the cell further prepares to
divide the replicated genome linked to
many safeguards in mitosis before split-
ting into 2 daughter cells. Glucose is the
major energy source for cells, and the
determination of lactate and carbon diox-
ide production from glucose in con-
trolled batch cultures has led to an
estimate that 2 × 1012 ATPs are required
to make a mouse LS cell.5 As such, a
central regulator of cell growth and pro-
liferation such as MYC must have the
ability to stimulate energy uptake, bio-
synthetic events, and cell cycle progres-
sion in a temporally coordinated manner
within a vast network of other regulatory
molecules (Figures 1 and 2).
Now that the Myc transcription factor
is established as a bona fide conductor
of the symphony of metabolism, cell
growth, and proliferation (Figure 1), it is
not surprising in retrospect that v-myc
was among the first oncogenes to be
identified because of its pleiotropic
effects on many different cellular func-
tions and its central role in tumorigene-
sis.6,7 The proto-oncogene MYC is
highly regulated under the extreme scru-
tiny of a large variety of signal transduc-
tion pathways culminating in a cast of
transcription factors that orchestrate
MYC expression through canonical
B-DNA binding sites or through more
elaborate DNA structures such as the
G-quadruplex in regulatory regions of
the MYC gene8 (Levens,9 this issue).
Division of Hematology, Department of Medicine,
and Departments of Cell Biology, Oncology,
Pathology, and Molecular Biology & Genetics, The
Sidney Kimmel Comprehensive Cancer Center at
Johns Hopkins, Johns Hopkins University School of
Medicine, Baltimore, MD, USA
Chi V. Dang, Ross Research Building, Room 1032,
720 Rutland Avenue, Baltimore, MD 21205; email:
Enigmatic MYC Conducts an Unfolding
Systems Biology Symphony
Chi V. Dang
Genes & Cancer
1(6) 526 –531
© The Author(s) 2010
Reprints and permission:
Far-reaching and enigmatic MYC / Dang
through the WNT or Notch pathway
results, respectively, in β -catenin or
Notch intracellular domain–mediated
transcriptional activation of MYC expres-
sion (Figure 1). TGFβ , on the other hand,
can attenuate MYC expression through
Smad transcription factors (Figure 1).
Normal MYC is hence part of a highly
adaptive and flexible network of many
regulatory molecules that are tweaked
by cues external to the cell, such that
when growth signals abate, receptors
and cytoplasmic integrators respond,
MYC expression diminishes, and cells
become dormant (Figures 2 and 3).
In the flexible but regulated normal
cellular network, the orchestration of
regulatory molecules relies on feed-back
and feed-forward loops that control their
levels through synthesis, posttransla-
tional modification, or degradation in
a temporally coordinated manner.10,11
When normal cells are replenished in
damaged tissues by tissue stem cells or
in tissues that have a naturally high
example, signal transduction turnover rate, the extracellular matrix and
growth factors engage a variety of recep-
tors to trigger a response leading to
increased energy uptake and enhanced
biosynthetic events for cell growth in
preparation for entry into S phase (Fig-
ures 2 and 3).12 In contrast, when natural
mutations result in the activation of
oncogenes such as MYC, high levels of
Myc trigger checkpoints that eliminate
the deranged cell through cell death.
However, when accompanying muta-
tions subdue the programmed suicidal
tendency so that cells are able to survive
even with high MYC levels, cancer cells
emerge.13 In this setting, deregulated
MYC reprograms the highly flexible
normal network to one that is rigidly
linked to heightened MYC activity,
which is not subject to the editing func-
tion of external cues (Figure 3). In par-
ticular, it is envisioned that a sustained
increase in MYC activity results in a dis-
torted network of regulatory molecules
whose levels and regulation are repro-
grammed, such that removal of MYC
activity from this altered network could
cause an uncoordinated decay of the
regulatory nodes, resulting in an imbal-
anced network that culminates in chaos
and cell death, otherwise known as
oncogene addiction14 (Felsher,15 this
issue). What then is the function of Myc,
and how does a flexible network with a
tunable MYC gene in normal cells differ
from one in which MYC is locked at a
high volume in cancer cells?
The MYC gene produces a helix-
loop-helix leucine zipper transcription
factor, Myc, that dimerizes with Max
to bind DNA and regulate transcription
through recruiting cofactors and initiat-
ing transcription or alleviating tran-
scriptional pause.7,16 Myc also has
nontranscriptional roles including its
involvement in mRNA capping (Cowling
& Cole,17 this issue) and DNA replica-
tion.18 Further, the Max network of pro-
teins, which can dimerize with Mad
proteins to antagonize some of Myc’s
function,19 has related family members
such as Mlx, which dimerizes with
Mondo proteins, one of which is
involved in the regulation of energy
metabolism20 (Sloan & Ayer,21 this issue).
Myc also mediates transcriptional repres-
sion through its direct interaction with
Miz-17 (Herkert & Eilers,22 this issue),
activation of microRNAs23 (Bui & Men-
dell,24 this issue), or yet-undefined mech-
anisms that require tethering of Myc to
noncanonical Myc binding sites. As for
its transcriptional role, the target genes of
Myc have been a key focus for the field
that began with low-throughput subtrac-
tion cloning approaches to the current high-
throughput use of microarrays and deep
sequencing of chromatin immunoprecipi-
tated DNA25 (McMahon,26 this issue).
Intriguingly, although Myc has been
found to bind to thousands of binding
sites corresponding to thousands of
genes, only a minority of the bound genes
respond to Myc, as seen in several experi-
mental systems.27,28 In this regard, the
theme that multiple transcription factors
are required to fire off transcription is
beginning to emerge with the ability to
use high-throughput ChIP identification
of binding sites. Even with these
Figure 1. The MYC gene is depicted downstream of different signal transduction pathways, such
as WNT, Notch, receptor tyrosine kinases (RTK), and TGFβ. The MYC gene produces the Myc
transcription factor, which dimerizes with Max, recruits TFIIH, and stimulates RNA polymerase
activity to activate target genes. Myc affects diverse types of target genes regulated by RNA
polymerases I, II, and III as illustrated.
Genes & Cancer / vol 1 no 6 (2010)
powerful technologies, the universe of
Myc target genes in a variety of systems
is sizeable and bewildering with genes
involved in diverse cellular functions.
The network of Myc target genes
becomes even more complex with the
documentation that Myc also regulates
noncoding RNAs. Myc regulates micro-
RNAs, which are 22- to 23-nucleotide
long RNAs that modulate mRNA half-
lives or translation and can affect up
to hundreds of mRNAs23 (Bui &
Mendell,24 this issue). Moreover, not
only does Myc regulate RNA poly-
merase II genes but it also regulates
rRNAs through RNA polymerase I and
small RNAs through RNA polymerase
III.29 Thus, Myc uses a variety of tactics
to regulate multiple components of the
translational machinery, such as tRNAs,
aminoacyl-tRNA synthetases, and eIF4E
as well as mRNA capping via Myc’s
nontranscriptional activity, to ensure
that ribosome biogenesis is substantially
With an extremely large orchestra of
Myc target genes, which of these targets
plays the most important part of the
MYC symphony? It is doubtful that an
would highlight a certain orchestra
section over others, but it is well known
that there are 1st and 2nd strings, with
the leader of the 1st violin serving as the
concertmaster, subordinate only to the
conductor. In this regard, each section of
the orchestra (brass, percussion, strings,
and woodwinds) is necessary but not
sufficient for the conductor to execute a
symphony. Further, the redundancies in
certain sections, such as strings, can
accommodate the loss of a single violin-
ist. As such, in the MYC symphony, no
individual player is sufficient to replace
MYC,31,32 but there are many key target
genes that are necessary for Myc’s role
in activating cell growth and prolifera-
tion.33 There are also Myc target genes
(such as JTV-1) that are neither suffi-
cient nor necessary,34 due to redundan-
cies in certain sections of Myc targets. A
glimpse into the potential key function
of Myc could be gleaned from phyloge-
netic analysis of conserved Myc func-
tion. In this regard, the discovery of
Drosophila dMyc opened up a genetic
vista into the primordial function of Myc
that would otherwise be too complex to
swiftly emerge from experiments with
mammalian systems35,36 (Bellosta &
Gallant,37 this issue). Diminutive fruit
flies with small body size and shortened
bristles are the result of a hypomorphic
allele of dMyc that phenocopies loss of
function in genes involved in ribosome
biogenesis.38-40 Hence, it is likely that
the primordial function of MYC is to
stimulate ribosome biogenesis, which
could be considered the strings and con-
certmaster of the MYC symphony.
As microarray data sets emerge from
the study of Myc and a related family
member, N-Myc, the link between Myc
activation and the expression of genes
involved in ribosome biogenesis in
mammalian cells becomes better estab-
lished.3,4,30 The role of ribosomes in
tumorigenesis was documented by the
delay in Myc-mediated lymphomagene-
sis and decreased mortality when only 1
copy of RpL24 is available.41 Because
the synthesis of ribosomes is a bioener-
getic liability when the demand for
energy exceeds availability, feedback
loops are built into the network such that
glucose deprivation can attenuate rRNA
gene expression epigenetically, thereby
down-regulating the pace of ribosome
production.42,43 As such, when MYC is
deregulated and genes involved in ribo-
some biogenesis are expressed constitu-
tively in disregard to the availability of
nutrients, this rigid network causes a cell
with deregulated MYC to be vulnerable
to nutrient deprivation (Figure 3). Anal-
ogously, a revved-up engine requires
effective fuel injection; otherwise, the
engine would burn out. Indeed, deregu-
lated MYC expression sensitizes cells to
both glucose and glutamine deprivation,
which trigger apoptosis.44-46 So in addi-
tion to checkpoints and feedback loops,
such as activation of TGFβ signaling,
that are activated when Myc is highly
overexpressed (Felsher, this issue15), the
deregulated expression of MYC could
also cause a metabolic demand from the
stimulation of ribosome synthesis and
other biosynthetic processes, which, if
not sustained, will trigger cell death.
The requirement for increased meta-
bolic demand via Myc’s induction of
ribosome biogenesis is met by the ability
of Myc to induce the expression of genes
involved in both glucose and glutamine
Figure 2. Schema of receptor signaling through cytoplasmic integrators such as mTORC1,
mTORC2, and AKT or other relays that stimulate MYC expression. The cytoplasmic integrators
through posttranscriptional modification of substrate proteins or Myc via activation of target genes
can stimulate a cellular response that increases the uptake of energy and anabolic building blocks
to support translation for cell growth and proliferation.
Far-reaching and enigmatic MYC / Dang
metabolism47,48 (Sloan & Ayer,21 this
issue). A key difference between normal
and Myc-driven cancer cells is that
cells would trigger a network response
that causes MYC itself to be silenced,
withdrawal from normal
permitting the cell to retreat into a rest-
ing state. In contrast, when MYC is
deregulated, nutrient withdrawal cannot
attenuate MYC levels, which constitu-
tively signal the cell to build and build
for growth sake in a manner discon-
nected from the cellular energetic fiscal
reality, much like the overbloated hous-
ing market, which crashed with the real-
ization that the financial fuel was just an
illusion. Deregulated MYC hence causes
Myc-transformed cells to be addicted to
nutrients such as glucose and gluta-
mine.48 It is surmised from the concepts
derived here from the study of cells in
culture that oncogene addiction, particu-
larly addiction of tumors to Myc in
genetically engineered mouse models
(Felsher, this issue15), could well be due
to a more rigid network that drives cells
to grow and become more dependent on
nutrients. In this regard, removal of Myc
is accompanied by an asynchronous tun-
ing down of the cancer cell’s regulatory
network, culminating in an imbalance in
demand and resulting in cell death.
Analogously, when the orchestra direc-
tor prematurely leaves the hall at the
peak of a crescendo, the beat does not go
on, but rather the orchestra tumbles in
chaos and the symphony cacophonously
The understanding of Myc function
from the study of cells and model organ-
isms (Bellosta & Gallant37 and Felsher,15
this issue) has led to better insights into
the roles of Myc in human cancers such
as leukemias49 (Delgado & León,50 this
issue), breast cancer51,52 (Xu et al.,53 this
issue), and prostate cancer54 (De Marzo
et al.,55 this issue). In all of these differ-
ent settings, a common thread that puta-
tively connects these cancers is the
occurrence of hypertrophied nucleoli,
the site for ribosome biogenesis, in the
more aggressive cancers of each type.56
With MYC driving a significant portion
of human cancers and the realization
that many of these cancers might
be addicted to MYC, could Myc or
its target genes provide novel therapeu-
tic opportunities? In this regard, target-
ing MYC expression itself through
Figure 3. Conceptual normal and cancer cell networks are depicted as starburst nodes linked
by edges (lines). (A) The normal cell has a maintenance resting cell network, composed of key
housekeeping subnetworks (purple and black starbursts), and is depicted to acquire an increase in
the Myc network of genes with growth factor signaling. Myc further induces the energy metabolic
network of genes to support the concurrent activation of genes involved in ribosome biogenesis
(Ribi), a metabolically demanding node. Once committed into cycle, the cell replicates and divides
into daughter cells. (B) Example of a deregulated Myc-driven cancer cell network, in which the Myc
network of target genes is deregulated constitutively. The Myc-driven cancer cell is depicted with
decreased dependency on growth factors and constitutive activation of Ribi genes concurrently
with genes stimulating cellular uptake of energy and anabolic building blocks. When energy supply
is sufficient, the cancer cells continue to divide. In energy-limiting conditions, metabolic demand
outstrips energy availability, culminating in asynchrony and cell death.
Genes & Cancer / vol 1 no 6 (2010)
pharmacological manipulation of the
G-quadruplex57 (Hurley & Brooks,58
this issue), drug-mediated disruption of
tion59-61 (Prochownik & Vogt,62 this
issue), or manipulation of microRNA
Myc target genes themselves hold prom-
ise for new classes of anticancer drugs63
(Frenzel et al.,64 this issue).
Although novel approaches have per-
mitted a glimpse of the conductor and wiz-
ard behind the curtain, the enigmatic MYC
oncogene is likely still to hold back some
deeply held secrets from our quest to
understand its contribution to normal, can-
cer, and stem cell growth and proliferation.
For example, although our understanding
of how Myc stimulates cell growth and
proliferation is coming into sharper focus,
our knowledge of how Myc collaborates
with other transcription factors65 and how
Myc suppresses terminal differentiation
remains rudimentary.66,67 Further, whether
chromosome 8q24–associated cancers
will be susceptible to therapies targeting
MYC remains to be delineated (Grisanzio
& Freedman,68 this issue). Our substantial
understanding of the MYC oncogene,
some 30 years after its discovery, has
established a foundation to begin to trans-
late basic observations about this gene for
cancer therapy in the clinic.64 Perhaps
there will be a branch in the road ahead,
where taking the one not taken might
reveal some additional secrets held by the
enigmatic MYC oncogene.
Acknowledgments and Funding
I limited many of the references to review articles and
hence unintentionally omitted important primary
articles. I thank Debbie Johnson and Vanessa Dang
for comments. Our original work is supported by
NCI, NIH, Leukemia and Lymphoma Foundation,
and the Stand-Up-to-Cancer AACR initiative.
Declaration of Conflicting Interests
C.V.D. is a consultant for Agios Pharmaceuticals, Inc.
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