1. Introduction
2. The MYC family and the discovery of MYCN
The eventual discovery of
Neuroblastoma is the most common extracranial solid tumour of early childhood and accounts for approximately 15% of all cancer related deaths in children. Aggressive drug refractory neuroblastoma cells have been frequently observed to contain genomic aberrations referred to as double-minute chromatin bodies and homogeneously staining regions. Both of these types of aberrations were found to contain multiple copies or amplification of specific genes, and in particular, the critical gene within these regions was later identified to be the
All three tumour-associated
3. The functional activity of MYCN
MYC proteins are well established as nuclear phosphoproteins that act as regulators of transcription, and can both activate and repress the expression of its target genes [16].
The amino or N-terminus of MYCN acts as a transactivation domain that contains two highly conserved regions called Myc Homology Boxes I and II (MBI and MBII) [1]. This region has been shown to bind to nuclear cofactors, including TRRAP, p107, BIN1, MM-1, AMY-1, PAM, α-Tubulin, TIP48 and TIP49, to assist the targeting of protein to specific gene promoters [23, 25]. Another protein YAF2, has been demonstrated to bind to the central region of MYCN to further stimulate transcription upon MYCN-MAX transactivation [26]. All of these interacting proteins are a part of a transcription factor complex by which target genes are activated. Myc Homology Box III (MBIII) is conserved only within c-MYC and MYCN, but not MYCL, and is necessary for cellular transformation [27]. A fourth Myc Homology Box (MBIV) is also necessary for MYC transforming activity [28].
Recent studies have provided evidence of a function of MYCN that is independent from its role as a classical transcription factor. MYCN was shown to remodel large domains of euchromatin, regions of lightly packaged chromatin that contain active, functioning genes, by regulating histone acetylation [29, 30]. Two possibilities have been suggested for this role. The first is that MYCN maintains the activity of euchromatin, whilst the second is that MYCN maintains euchromatin at remote sites to act as an enhancer and regulator of genes at a distance. Novel functions of other MYC proteins have been identified through mutational analyses that have uncoupled the transforming ability of c-MYC from its role as a transcription factor [28, 31]. c-MYC was found to increase the translation of specific mRNAs by promoting the methylation of the 5’ mRNA guanine “cap”, including mRNAs encoding cyclin T1 and CDK9 [31]. A role for c-MYC has also been described in the initiation of DNA replication by binding to various components of the pre-replicative complex and localising to early sites of DNA replication [32]. These observations suggest that c-MYC may play a role in controlling initiation of the S phase of the cell cycle and contribute to replicative stress and genomic instability, to further accelerate tumorigenesis [17]. Even though the evidence has yet to be provided, given the high level of homology between c-MYC and MYCN, the described transcription-independent roles of c-MYC suggest similar roles will be identified for MYCN in contributing to tumour cell biology.
4. MYCN as a transcriptional activator
As indicated above, MYCN heterodimerises with MAX and binds with high affinity to a CACA/GTG E-box sequence found upstream of promoter target sequences [13]. The MYCN-MAX heterodimer activates transcription via several mechanisms. TRRAP (or TRansactivation/tRansformation Associated Protein) binds to the N-terminal region of MYCN and is essential for MYCN transformation. Through TRRAP, MYCN recruits histone acetylation (HAT) complexes to chromatin, including the 1.8 megaDalton SAGA complex (SPT/ADA/GCN5/Acetyltransferase) [33]. Histone acetylation is associated with gene activation by chromatin modification influencing histone-DNA and histone-histone contact [34]. TRRAP is involved with another HAT complex, TIP60, an H2A/H4 acetylase [35]. Interestingly,
The MYC family represents a particularly unusual set of transcription factors in that they can bind to and regulate approximately 10-15% of the entire genome [14]. Some MYCN target genes have been shown to be activated independently of TRRAP and HAT complexes. Investigation into HAT independent activation has revealed the involvement of RNA polymerase II at the promoter regions of target genes. c-MYC protein binding has been shown to stimulate the clearance of RNA polymerase II from the promoter region to allow for efficient transcription elongation by the RNA pol II kinases, TFIIH and positive transcription elongation factor b (PTEFb) [38]. c-MYC also regulates RNA pol II promoter clearance by controlling the expression of RNA pol II kinases via mRNA cap methylation, polysome loading, and the rate of translation [31].
5. MYCN as a transcriptional repressor
Most studies have focused on the role of MYC proteins as transcriptional activators. However, cells transformed by constitutive expression of c-MYC are characterised by the loss of expression of numerous genes such as those involved in cell adhesion and cell cycle regulation, and even loss of
The understanding of transcriptional repression by MYC proteins was greatly advanced via the identification of repressed target genes such as
6. Mechanisms of regulating MYCN expression
Due to the gross transforming ability of deregulated expression of MYC proteins, the expression of these protooncogenes is tightly regulated in normal cells at both the transcriptional and protein level. For example, MYC mRNA transcripts and proteins have very short half-lives and are expressed at constant levels as cells enter the cell cycle [56, 57]. Furthermore, anti-proliferative signals trigger rapid down-regulation in expression, and the phosphorylation patterns of MYC proteins are known to influence their stability. In addition to these mechanisms, expression of MYCN is particularly tightly regulated with regards to timing and tissue specificity. Thus, MYCN is normally expressed during embryonal development of the peripheral nervous system in neural crest cells [2]. Neural crest cells migrate during mid-gestation to populate the entire peripheral nervous system, including autonomic and peripheral ganglia and the adrenal gland. These migrating progenitor cells represent a highly proliferative population, and during normal development exit the cell-cycle and undergo differentiation following the colonisation to the ganglia and spinal cord area. This event is orchestrated by extracellular signalling molecules such as mitogens and cytokines and coincides with decreased expression of MYCN [56, 58]. Without this strict control, dysregulated MYCN expression impairs the ability of progenitor cells to undergo differentiation. Studies which sustained MYCN expression in murine neural crest cells under the control of a tyrosine hydroxylase promoter, demonstrated the capacity to cause neuroblastoma in transgenic mice [3]. Despite this transforming ability, MYCN is vital for normal embryonic development, and murine embryos lacking MYCN exhibit profound hypoplasia, particularly in the central and peripheral nervous system, disorganized architecture of the brain, defective heart development and defects in the lung, genitourinary system, stomach, intestines and limb buds [59].
In order to understand how extracellular stimuli controlled MYC expression in cells, gene mapping studies in association with
A key finding was made in 1986 which identified
Transcription alone cannot account for the large difference in mRNA levels following the introduction of proliferative or anti-proliferative stimuli. The rapid turnover of mRNA was also associated with the discovery of two distinct mechanisms of
7. Regulation of MYCN protein expression
The regulation of MYCN protein levels has also been investigated and phosphopeptide analysis has revealed that specific serine and threonine residues of MYCN are phosphorylated
8. MYCN downstream target genes
The first transcriptional target for a MYC protein was discovered ten years after the identification of human
Expression microarrays and chromatin immunoprecipitation assays (ChIP) have helped researchers identify MYC-regulated targets as well as link MYC-target expression to functional cellular pathways which are associated with transformation [79, 80]. MYC and MYCN-regulated targets have since been linked to a number of transforming activities involving the cell cycle (eg. cyclin D2, CDK4, p21), cell proliferation (e.g. MDM2), growth, metabolism (e.g. ribosomal proteins, proteins involved in nucleotide biosynthesis such as thymidylate synthase and ODC1), cell adhesion and migration (e.g. integrins) and angiogenesis (e.g. thrombospondin) [81-86]. Indeed, the activation and repression of MYC target genes is a well-coordinated event. Time course studies using microarray have identified differences between early and delayed gene expression responses, following MYC activation in a MYC-inducible cell system [87]. Early-response MYC target genes are primarily involved in MAPK signalling, RNA metabolism and transcription factors, which suggests a program that prepares cells for entry into the S phase. On the other hand, delayed-response MYC target genes are involved in ribosomal biogenesis, nucleotide metabolism and energy metabolism, suggesting subsequent maintenance of cells during the S phase. Finally, late steady-state MYC-mediated transcription involved genes that regulate the cell cycle, nucleotide metabolism and DNA replication. Most genes that were activated in the early response were then repressed during this late steady-state phase. Furthermore, sustained MYC activation led to the silencing of differentiation-related genes and upregulation of genes that are involved cell proliferation.
During tumorigenesis, MYCN promotes cell cycle progression by the activation of cyclins (such as cyclin D1 and D2) as well as cyclin-dependent kinase 4 (CDK4), and represses the expression of mediators of cell cycle arrest such as p21 [73]. One important MYCN-regulated metabolic pathway involves the synthesis of polyamines, which are organic cations that enhance transcription, translation and replication [88].
Another gene whose expression is strongly correlated with
9. MYCN tumorigenesis
The evidence for a clinical role of MYCN in the tumorigenesis of neuroblastoma was first recognised when the amplification of the
The
The potent transforming ability of MYCN has been demonstrated by several studies, while
Whilst
Although the majority of the literature investigating
The most compelling evidence for a role of MYCN in the biology of medulloblastoma comes from two mouse models of this disease. Firstly, targeted expression of MYCN to the cerebellum in transgenic mice has demonstrated the importance of MYCN in contributing to the initiation and progression of medulloblastoma and also in the metastatic spread of disease to the spinal and paraspinal tissues via cerebral spinal fluid. Furthermore, the MYCN downstream targets Odc1, MDM2 and Fb1 were upregulated and correlated with
10. Molecular targeting of MYCN for therapeutic benefit
Molecular targeted therapy involves targeting malignant cell growth by directly inhibiting the function of specific molecules within a cell, namely those that are responsible for driving cancer progression. Such agents aim to block or exploit various aspects of cancer biology, such as genetic instability, proliferative signal transduction, aberrant cell cycle control, deregulated survival, angiogenesis and metastasis [121]. Numerous methods of molecular targeted therapy have been investigated, including antisense oligonucleotides (ASOs) that hybridise to and inhibit the mRNA of a specific gene; peptide nucleic acids (PNAs), which are DNA analogues that specifically hybridise to DNA and/or RNA in a complementary manner to inhibit transcription/translation of a target gene; and small interfering RNA (siRNA), which silences gene expression by inducing the sequence specific degradation of complementary mRNA or by inhibiting translation [122]. However, such technologies although useful in the laboratory, have had limited success in the clinic due to problems associated with their delivery.
Immunotherapy has also generated interest, and utilises the body’s immune system to target and remove cancer cells by the recognition of certain molecular markers, or block specific cell receptor pathways. Another approach to molecular targeting, involves the development of synthetic small molecule inhibitors which potentially have the ability to interfere with a molecular target at multiple levels [122]. These small molecules may diffuse into cells to act directly on intracellular targets, such as inhibiting the expression of a target gene at the transcriptional or translational level, or inhibiting the function of a protein by directly binding to the protein and inducing conformational changes that prevent its interaction with other factors [123]. Synthetic small molecules are generally defined by a molecular weight cut-off of <500Da. They are favoured by the pharmaceutical industry because of their attractive pharmacokinetic properties, especially tumour cell penetration, and their relative ease of development and pharmaceutical production [123]. At present, strategies to develop novel small molecule inhibitors as viable therapies are aimed at using these technologies in combination with other cytotoxic drugs, with the hope of reducing drug dosages, and thus overcoming drug resistance associated with intensive chemotherapy, and reducing drug-related toxicity and side effects.
A number of molecular mechanisms have been identified as possible targets for the treatment of neuroblastoma. However, the prominent deregulated expression and amplification of
Inhibition of MYCN protein through its protein-protein interactions and protein-DNA interactions was previously seen as too difficult to target by small molecules [128]. However, it has been reported that small-molecule antagonists of MYC/MAX dimerisation interfered with c-MYC-induced oncogenic transformation of chicken embryo fibroblasts
11. Future perspectives
The validity for targeting MYCN for therapeutic benefit relies on the gross transforming ability of this transcription factor. MYCN represents a particularly attractive target due to its lack of expression in adult and normal paediatric tissues. Although MYCN, and MYC proteins in general are commonly viewed as “undruggable” due to the nature of these proteins, MYCN offers potential advantages at a number of levels for therapeutic inhibition, either upstream, or downstream along the MYCN transcriptional pathway. If clinically useful MYCN inhibitors can be successfully developed, they are likely to find application in combination therapies involving conventional chemotherapeutic drugs and be used as an improved approach to target aggressive cancers that are driven by this oncoprotein.
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