Special Issue "MYC Networks"

A special issue of Genes (ISSN 2073-4425). This special issue belongs to the section "Human Genomics and Genetic Diseases".

Deadline for manuscript submissions: closed (28 February 2017).

Special Issue Editor

Guest Editor
Dr. Daitoku Sakamuro

Associate Professor, Department of Biochemistry and Molecular Biology, Medical College of Georgia and Georgia Cancer Center, Augusta University, 1410 Laney Walker Blvd., Augusta, GA 30912, USA
Website | E-Mail
Phone: +1 706 (721) 1018
Interests: c-MYC; E2F1; BIN1; PARP1; RB1; transcriptional corepressor; oncogenes; tumor suppressors; genomic instability; serum starvation; apoptosis (including anoikis); cancer chemosensitivity

Special Issue Information

Dear Colleagues,

Regardless of its comprehensive and in-depth study over more than three decades, the c-MYC protein is still biologically an enigmatic topic of research. The protein plays a central role in various cellular functions, including cell-cycle progression, de-differentiation, genomic instability, apoptosis, and metabolism, but also in recently-emerged research areas, such as pluripotency in iPS and cancer stem cells, epigenetic gene regulation, chromatin remodeling, RNA splicing, and immune response. As a bona fide oncogenic transcription factor, c-MYC has also been recognized as a fascinating anticancer therapeutic target. However, the precise mechanism(s) through which c-MYC properly exerts its divergent cellular functions remain obscure. It is significant to better understand direct and indirect regulatory/effector molecules of c-MYC pathways and protein components in c-MYC-containing high-molecular-weight complexes: It may provide conceptually a new anticancer drug design target in cancers addicted to c-MYC.

In this Special Issue, we would like to invite submission of original research or review articles on any topic related to the “c-MYC Networks”, through which we hope to explore new horizons of the thrilling functions of c-MYC in normal tissue development and tumorigenesis.

We look forward to receiving your contributions.

Dr. Daitoku Sakamuro
Guest Editor

Manuscript Submission Information

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Keywords

  • gene transactivation vs. transrepression
  • protein translation
  • cell-cycle progression and cellular transformation
  • apoptosis, autophagy, and anoikis
  • genomic instability vs. cancer chemoresistance
  • cancer metabolism
  • c-MYC-induced de-differentiation and iPS formation
  • RNA splicing
  • chromatin remodeling and epigenetics
  • MYC family and human cancer
  • MYC and cancer immunotherapy

Published Papers (18 papers)

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Research

Jump to: Review

Open AccessArticle
MB0 and MBI Are Independent and Distinct Transactivation Domains in MYC that Are Essential for Transformation
Received: 10 February 2017 / Revised: 24 April 2017 / Accepted: 28 April 2017 / Published: 6 May 2017
Cited by 2 | PDF Full-text (4313 KB) | HTML Full-text | XML Full-text
Abstract
MYC is a transcription factor that is essential for cellular proliferation and development. Deregulation or overexpression of MYC occurs in a variety of human cancers. Ectopic expression of MYC causes hyperproliferation and transformation of cells in culture and tumorigenesis in several transgenic mouse [...] Read more.
MYC is a transcription factor that is essential for cellular proliferation and development. Deregulation or overexpression of MYC occurs in a variety of human cancers. Ectopic expression of MYC causes hyperproliferation and transformation of cells in culture and tumorigenesis in several transgenic mouse models. Deregulation of MYC can also induce apoptosis through activation of p53 and/or ARF tumor suppressors as a safeguard to prevent tumorigenesis. MYC binds to thousands of genomic sites and regulates hundreds of target genes in a context-dependent fashion to mediate these diverse biological roles. The N-terminal region of MYC contains several conserved domains or MYC Boxes (MB), which influence the different MYC transcriptional and biological activities to varying degrees. However, the specific domains that mediate the ability of MYC to activate transcription remain ill defined. In this report, we have identified a new conserved transactivation domain (TAD), MB0, which is essential for MYC transactivation and target gene induction. We demonstrate that MB0 and MBI represent two distinct and independent TADs within the N-terminal 62 amino acids of MYC. In addition, both MB0 and MBI are essential for MYC transformation of primary fibroblasts in cooperation with activated RAS, while MB0 is necessary for efficient MYC-induced p53-independent apoptosis. Full article
(This article belongs to the Special Issue MYC Networks)
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Open AccessArticle
The Stearoyl-CoA Desaturase-1 (Desat1) in Drosophila cooperated with Myc to Induce Autophagy and Growth, a Potential New Link to Tumor Survival
Received: 27 March 2017 / Revised: 21 April 2017 / Accepted: 21 April 2017 / Published: 28 April 2017
Cited by 3 | PDF Full-text (7189 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Lipids are an important energy supply in our cells and can be stored or used to produce macromolecules during lipogenesis when cells experience nutrient starvation. Our proteomic analysis reveals that the Drosophila homologue of human Stearoyl-CoA desaturase-1 (Desat1) is an indirect target of [...] Read more.
Lipids are an important energy supply in our cells and can be stored or used to produce macromolecules during lipogenesis when cells experience nutrient starvation. Our proteomic analysis reveals that the Drosophila homologue of human Stearoyl-CoA desaturase-1 (Desat1) is an indirect target of Myc in fat cells. Stearoyl-CoA desaturases are key enzymes in the synthesis of monounsaturated fatty acids critical for the formation of complex lipids such as triglycerides and phospholipids. Their function is fundamental for cellular physiology, however in tumors, overexpression of SCD-1 and SCD-5 has been found frequently associated with a poor prognosis. Another gene that is often upregulated in tumors is the proto-oncogene c-myc, where its overexpression or increased protein stability, favor cellular growth. Here, we report a potential link between Myc and Desat1 to control autophagy and growth. Using Drosophila, we found that expression of Desat1, in metabolic tissues like the fat body, in the gut and in epithelial cells, is necessary for Myc function to induce autophagy a cell eating mechanism important for energy production. In addition, we observed that reduction of Desat1 affects Myc ability to induce growth in epithelial cells. Our data also identify, in prostatic tumor cells, a significant correlation between the expression of Myc and SCD-1 proteins, suggesting the existence of a potential functional relationship between the activities of these proteins in sustaining tumor progression. Full article
(This article belongs to the Special Issue MYC Networks)
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Open AccessArticle
c‐Myc‐Induced Survivin Is Essential for Promoting  the Notch‐Dependent T Cell Differentiation from  Hematopoietic Stem Cells
Received: 1 January 2017 / Accepted: 28 February 2017 / Published: 6 March 2017
Cited by 6 | PDF Full-text (5743 KB) | HTML Full-text | XML Full-text
Abstract
Notch is indispensable for T cell lineage commitment, and is needed for thymocyte differentiation at early phases. During early stages of T cell development, active Notch prevents other lineage potentials including B cell lineage and myeloid cell (e.g., dendritic cell) lineage. Nevertheless, the [...] Read more.
Notch is indispensable for T cell lineage commitment, and is needed for thymocyte differentiation at early phases. During early stages of T cell development, active Notch prevents other lineage potentials including B cell lineage and myeloid cell (e.g., dendritic cell) lineage. Nevertheless, the precise intracellular signaling pathways by which Notch promotes T cell differentiation remain unclear. Here we report that the transcription factor c‐Myc is a key mediator of the Notch signaling–regulated T cell differentiation. In a well‐established in vitro differentiation model of T lymphocytes from hematopoietic stem cells, we showed that Notch1 and 4 directly promoted c‐Myc expression; dominant‐negative (DN) c‐Myc inhibited early T cell differentiation. Moreover, the c‐Myc expression activated by Notch signaling increased the expression of survivin, an inhibitor of apoptosis (IAP) protein. We further demonstrated that over‐expression of c‐Myc increased the abundance of survivin and the T cell differentiation thereof, whereas dn c‐Myc reduced survivin levels and concomitantly retarded the differentiation. The c‐Myc–dependent survivin induction is functionally germane, because Notch‐dependent T cell differentiation was canceled by the depletion of survivin. These results identify both c‐Myc and survivin as important mediators of the Notch signaling–regulated differentiation of T lymphocytes from hematopoietic stem cells. Full article
(This article belongs to the Special Issue MYC Networks)
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Review

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Open AccessReview
MYC Modulation around the CDK2/p27/SKP2 Axis
Received: 29 May 2017 / Revised: 23 June 2017 / Accepted: 24 June 2017 / Published: 30 June 2017
Cited by 15 | PDF Full-text (3422 KB) | HTML Full-text | XML Full-text
Abstract
MYC is a pleiotropic transcription factor that controls a number of fundamental cellular processes required for the proliferation and survival of normal and malignant cells, including the cell cycle. MYC interacts with several central cell cycle regulators that control the balance between cell [...] Read more.
MYC is a pleiotropic transcription factor that controls a number of fundamental cellular processes required for the proliferation and survival of normal and malignant cells, including the cell cycle. MYC interacts with several central cell cycle regulators that control the balance between cell cycle progression and temporary or permanent cell cycle arrest (cellular senescence). Among these are the cyclin E/A/cyclin-dependent kinase 2 (CDK2) complexes, the CDK inhibitor p27KIP1 (p27) and the E3 ubiquitin ligase component S-phase kinase-associated protein 2 (SKP2), which control each other by forming a triangular network. MYC is engaged in bidirectional crosstalk with each of these players; while MYC regulates their expression and/or activity, these factors in turn modulate MYC through protein interactions and post-translational modifications including phosphorylation and ubiquitylation, impacting on MYC’s transcriptional output on genes involved in cell cycle progression and senescence. Here we elaborate on these network interactions with MYC and their impact on transcription, cell cycle, replication and stress signaling, and on the role of other players interconnected to this network, such as CDK1, the retinoblastoma protein (pRB), protein phosphatase 2A (PP2A), the F-box proteins FBXW7 and FBXO28, the RAS oncoprotein and the ubiquitin/proteasome system. Finally, we describe how the MYC/CDK2/p27/SKP2 axis impacts on tumor development and discuss possible ways to interfere therapeutically with this system to improve cancer treatment. Full article
(This article belongs to the Special Issue MYC Networks)
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Open AccessReview
The Dual Roles of MYC in Genomic Instability and Cancer Chemoresistance
Received: 28 February 2017 / Revised: 31 May 2017 / Accepted: 1 June 2017 / Published: 7 June 2017
Cited by 5 | PDF Full-text (616 KB) | HTML Full-text | XML Full-text
Abstract
Cancer is associated with genomic instability and aging. Genomic instability stimulates tumorigenesis, whereas deregulation of oncogenes accelerates DNA replication and increases genomic instability. It is therefore reasonable to assume a positive feedback loop between genomic instability and oncogenic stress. Consistent with this premise, [...] Read more.
Cancer is associated with genomic instability and aging. Genomic instability stimulates tumorigenesis, whereas deregulation of oncogenes accelerates DNA replication and increases genomic instability. It is therefore reasonable to assume a positive feedback loop between genomic instability and oncogenic stress. Consistent with this premise, overexpression of the MYC transcription factor increases the phosphorylation of serine 139 in histone H2AX (member X of the core histone H2A family), which forms so-called γH2AX, the most widely recognized surrogate biomarker of double-stranded DNA breaks (DSBs). Paradoxically, oncogenic MYC can also promote the resistance of cancer cells to chemotherapeutic DNA-damaging agents such as cisplatin, clearly implying an antagonistic role of MYC in genomic instability. In this review, we summarize the underlying mechanisms of the conflicting functions of MYC in genomic instability and discuss when and how the oncoprotein exerts the contradictory roles in induction of DSBs and protection of cancer-cell genomes. Full article
(This article belongs to the Special Issue MYC Networks)
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Open AccessReview
MYC Deregulation in Primary Human Cancers
Received: 23 March 2017 / Revised: 19 May 2017 / Accepted: 19 May 2017 / Published: 25 May 2017
Cited by 48 | PDF Full-text (3643 KB) | HTML Full-text | XML Full-text
Abstract
MYC regulates a complex biological program by transcriptionally activating and repressing its numerous target genes. As such, MYC is a master regulator of many processes, including cell cycle entry, ribosome biogenesis, and metabolism. In cancer, the activity of the MYC transcriptional network is [...] Read more.
MYC regulates a complex biological program by transcriptionally activating and repressing its numerous target genes. As such, MYC is a master regulator of many processes, including cell cycle entry, ribosome biogenesis, and metabolism. In cancer, the activity of the MYC transcriptional network is frequently deregulated, contributing to the initiation and maintenance of disease. Deregulation often leads to constitutive overexpression of MYC, which can be achieved through gross genetic abnormalities, including copy number alterations, chromosomal translocations, increased enhancer activity, or through aberrant signal transduction leading to increased MYC transcription or increased MYC mRNA and protein stability. Herein, we summarize the frequency and modes of MYC deregulation and describe both well-established and more recent findings in a variety of cancer types. Notably, these studies have highlighted that with an increased appreciation for the basic mechanisms deregulating MYC in cancer, new therapeutic vulnerabilities can be discovered and potentially exploited for the inhibition of this potent oncogene in cancer. Full article
(This article belongs to the Special Issue MYC Networks)
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Open AccessReview
MYC—Master Regulator of the Cancer Epigenome and Transcriptome
Received: 28 February 2017 / Revised: 9 May 2017 / Accepted: 10 May 2017 / Published: 13 May 2017
Cited by 23 | PDF Full-text (2798 KB) | HTML Full-text | XML Full-text
Abstract
Overexpression of MYC is a hallmark of many human cancers. The MYC oncogene has long been thought to execute its neoplastic functions by acting as a classic transcription factor, deregulating the expression of a large number of specific target genes. However, MYC’s influence [...] Read more.
Overexpression of MYC is a hallmark of many human cancers. The MYC oncogene has long been thought to execute its neoplastic functions by acting as a classic transcription factor, deregulating the expression of a large number of specific target genes. However, MYC’s influence on many of these target genes is rather modest and there is little overlap between MYC regulated genes in different cell types, leaving many mechanistic questions unanswered. Recent advances in the field challenge the dogma further, revealing a role for MYC that extends beyond the traditional concept of a sequence-specific transcription factor. In this article, we review MYC’s function as a regulator of the cancer epigenome and transcriptome. We outline our current understanding of how MYC regulates chromatin structure in both a site-specific and genome-wide fashion, and highlight the implications for therapeutic strategies for cancers with high MYC expression. Full article
(This article belongs to the Special Issue MYC Networks)
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Open AccessReview
c-MYC—Making Liver Sick: Role of c-MYC in Hepatic Cell Function, Homeostasis and Disease
Received: 7 February 2017 / Revised: 30 March 2017 / Accepted: 12 April 2017 / Published: 19 April 2017
Cited by 16 | PDF Full-text (593 KB) | HTML Full-text | XML Full-text
Abstract
Over 35 years ago, c-MYC, a highly pleiotropic transcription factor that regulates hepatic cell function, was identified. In recent years, a considerable increment in the number of publications has significantly shifted the way that the c-MYC function is perceived. Overexpression of c-MYC alters [...] Read more.
Over 35 years ago, c-MYC, a highly pleiotropic transcription factor that regulates hepatic cell function, was identified. In recent years, a considerable increment in the number of publications has significantly shifted the way that the c-MYC function is perceived. Overexpression of c-MYC alters a wide range of roles including cell proliferation, growth, metabolism, DNA replication, cell cycle progression, cell adhesion and differentiation. The purpose of this review is to broaden the understanding of the general functions of c-MYC, to focus on c-MYC-driven pathogenesis in the liver, explain its mode of action under basal conditions and during disease, and discuss efforts to target c-MYC as a plausible therapy for liver disease. Full article
(This article belongs to the Special Issue MYC Networks)
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Open AccessReview
MYC, Cell Competition, and Cell Death in Cancer: The Inseparable Triad
Received: 13 March 2017 / Revised: 9 April 2017 / Accepted: 12 April 2017 / Published: 17 April 2017
Cited by 7 | PDF Full-text (1218 KB) | HTML Full-text | XML Full-text
Abstract
Deregulation of MYC family proteins in cancer is associated with a global reprogramming of gene expression, ultimately promoting glycolytic pathways, cell growth, and proliferation. It is well known that MYC upregulation triggers cell-autonomous apoptosis in normal tissues, while frankly malignant cells develop resistance [...] Read more.
Deregulation of MYC family proteins in cancer is associated with a global reprogramming of gene expression, ultimately promoting glycolytic pathways, cell growth, and proliferation. It is well known that MYC upregulation triggers cell-autonomous apoptosis in normal tissues, while frankly malignant cells develop resistance to apoptotic stimuli, partly resulting from MYC addiction. As well as inducing cell-autonomous apoptosis, MYC upregulation is able to trigger non cell-autonomous apoptotic death through an evolutionarily conserved mechanism known as “cell competition”. With regard to this intimate and dual relationship between MYC and cell death, recent evidence obtained in Drosophila models of cancer has revealed that, in early tumourigenesis, MYC upregulation guides the clonal expansion of mutant cells, while the surrounding tissue undergoes non-cell autonomous death. Apoptosis inhibition in this context was shown to restrain tumour growth and to restore a wild-type phenotype. This suggests that cell-autonomous and non cell-autonomous apoptosis dependent on MYC upregulation may shape tumour growth in different ways, soliciting the need to reconsider the role of cell death in cancer in the light of this new level of complexity. Here we review recent literature about MYC and cell competition obtained in Drosophila, with a particular emphasis on the relevance of cell death to cell competition and, more generally, to cancer. Possible implications of these findings for the understanding of mammalian cancers are also discussed. Full article
(This article belongs to the Special Issue MYC Networks)
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Open AccessReview
Controlling the Master: Chromatin Dynamics at the MYC Promoter Integrate Developmental Signaling
Received: 27 January 2017 / Revised: 15 March 2017 / Accepted: 7 April 2017 / Published: 11 April 2017
Cited by 5 | PDF Full-text (1879 KB) | HTML Full-text | XML Full-text
Abstract
The transcription factor and cell growth regulator MYC is potently oncogenic and estimated to contribute to most cancers. Decades of attempts to therapeutically target MYC directly have not resulted in feasible clinical applications, and efforts have moved toward indirectly targeting MYC expression, function [...] Read more.
The transcription factor and cell growth regulator MYC is potently oncogenic and estimated to contribute to most cancers. Decades of attempts to therapeutically target MYC directly have not resulted in feasible clinical applications, and efforts have moved toward indirectly targeting MYC expression, function and/or activity to treat MYC-driven cancer. A multitude of developmental and growth signaling pathways converge on the MYC promoter to modulate transcription through their downstream effectors. Critically, even small increases in MYC abundance (<2 fold) are sufficient to drive overproliferation; however, the details of how oncogenic/growth signaling networks regulate MYC at the level of transcription remain nebulous even during normal development. It is therefore essential to first decipher mechanisms of growth signal-stimulated MYC transcription using in vivo models, with intact signaling environments, to determine exactly how these networks are dysregulated in human cancer. This in turn will provide new modalities and approaches to treat MYC-driven malignancy. Drosophila genetic studies have shed much light on how complex networks signal to transcription factors and enhancers to orchestrate Drosophila MYC (dMYC) transcription, and thus growth and patterning of complex multicellular tissue and organs. This review will discuss the many pathways implicated in patterning MYC transcription during development and the molecular events at the MYC promoter that link signaling to expression. Attention will also be drawn to parallels between mammalian and fly regulation of MYC at the level of transcription. Full article
(This article belongs to the Special Issue MYC Networks)
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Open AccessReview
The Role of c-MYC in B-Cell Lymphomas: Diagnostic and Molecular Aspects
Received: 13 January 2017 / Revised: 27 March 2017 / Accepted: 27 March 2017 / Published: 5 April 2017
Cited by 19 | PDF Full-text (2171 KB) | HTML Full-text | XML Full-text
Abstract
c-MYC is one of the most essential transcriptional factors, regulating a diverse array of cellular functions, including proliferation, growth, and apoptosis. Dysregulation of c-MYC is essential in the pathogenesis of a number of B-cell lymphomas, but is rarely reported in T-cell lymphomas. c-MYC [...] Read more.
c-MYC is one of the most essential transcriptional factors, regulating a diverse array of cellular functions, including proliferation, growth, and apoptosis. Dysregulation of c-MYC is essential in the pathogenesis of a number of B-cell lymphomas, but is rarely reported in T-cell lymphomas. c-MYC dysregulation induces lymphomagenesis by loss of the tight control of c-MYC expression, leading to overexpression of intact c-MYC protein, in contrast to the somatic mutations or fusion proteins seen in many other oncogenes. Dysregulation of c-MYC in B-cell lymphomas occurs either as a primary event in Burkitt lymphoma, or secondarily in aggressive lymphomas such as diffuse large B-cell lymphoma, plasmablastic lymphoma, mantle cell lymphoma, or double-hit lymphoma. Secondary c-MYC changes include gene translocation and gene amplification, occurring against a background of complex karyotype, and most often confer aggressive clinical behavior, as evidenced in the double-hit lymphomas. In low-grade B-cell lymphomas, acquisition of c-MYC rearrangement usually results in transformation into highly aggressive lymphomas, with some exceptions. In this review, we discuss the role that c-MYC plays in the pathogenesis of B-cell lymphomas, the molecular alterations that lead to c-MYC dysregulation, and their effect on prognosis and diagnosis in specific types of B-cell lymphoma. Full article
(This article belongs to the Special Issue MYC Networks)
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Open AccessReview
Role of MYC in B Cell Lymphomagenesis
Received: 30 January 2017 / Revised: 20 March 2017 / Accepted: 28 March 2017 / Published: 4 April 2017
Cited by 3 | PDF Full-text (1297 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
B cell lymphomas mainly arise from different developmental stages of B cells in germinal centers of secondary lymphoid tissue. There are a number of signaling pathways that affect the initiation and development of B cell lymphomagenesis. The functions of several key proteins that [...] Read more.
B cell lymphomas mainly arise from different developmental stages of B cells in germinal centers of secondary lymphoid tissue. There are a number of signaling pathways that affect the initiation and development of B cell lymphomagenesis. The functions of several key proteins that represent branching points of signaling networks are changed because of their aberrant expression, degradation, and/or accumulation, and those events determine the fate of the affected B cells. One of the most influential transcription factors, commonly associated with unfavorable prognosis for patients with B cell lymphoma, is nuclear phosphoprotein MYC. During B cell lymphomagenesis, oncogenic MYC variant is deregulated through various mechanisms, such as gene translocation, gene amplification, and epigenetic deregulation of its expression. Owing to alterations of downstream signaling cascades, MYC-overexpressing neoplastic B cells proliferate rapidly, avoid apoptosis, and become unresponsive to most conventional treatments. This review will summarize the roles of MYC in B cell development and oncogenesis, as well as its significance for current B cell lymphoma classification. We compared communication networks within transformed B cells in different lymphomas affected by overexpressed MYC and conducted a meta-analysis concerning the association of MYC with tumor prognosis in different patient populations. Full article
(This article belongs to the Special Issue MYC Networks)
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Open AccessReview
Targeting MYC Dependence by Metabolic Inhibitors in Cancer
Received: 6 January 2017 / Revised: 23 March 2017 / Accepted: 27 March 2017 / Published: 31 March 2017
Cited by 9 | PDF Full-text (526 KB) | HTML Full-text | XML Full-text
Abstract
Abstract: MYC is a critical growth regulatory gene that is commonly overexpressed in a wide range of cancers. Therapeutic targeting of MYC transcriptional activity has long been a goal, but it has been difficult to achieve with drugs that directly block its [...] Read more.
Abstract: MYC is a critical growth regulatory gene that is commonly overexpressed in a wide range of cancers. Therapeutic targeting of MYC transcriptional activity has long been a goal, but it has been difficult to achieve with drugs that directly block its DNA-binding ability. Additional approaches that exploit oncogene addiction are promising strategies against MYC-driven cancers. Also, drugs that target metabolic regulatory pathways and enzymes have potential for indirectly reducing MYC levels. Glucose metabolism and oxidative phosphorylation, which can be targeted by multiple agents, promote cell growth and MYC expression. Likewise, modulation of the signaling pathways and protein synthesis regulated by adenosine monophosphate-activated protein kinase (AMPK) and mechanistic target of rapamycin (mTOR) can also be an effective route for suppressing MYC translation. Furthermore, recent data suggest that metabolism of nucleotides, fatty acids and glutamine are exploited to alter MYC levels. Combination therapies offer potential new approaches to overcome metabolic plasticity caused by single agents. Although potential toxicities must be carefully controlled, new inhibitors currently being tested in clinical trials offer significant promise. Therefore, as both a downstream target of metabolism and an upstream regulator, MYC is a prominent central regulator of cancer metabolism. Exploiting metabolic vulnerabilities of MYC-driven cancers is an emerging research area with translational potential. Full article
(This article belongs to the Special Issue MYC Networks)
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Open AccessReview
The MYCN Protein in Health and Disease
Received: 31 January 2017 / Revised: 23 March 2017 / Accepted: 27 March 2017 / Published: 30 March 2017
Cited by 17 | PDF Full-text (1194 KB) | HTML Full-text | XML Full-text
Abstract
MYCN is a member of the MYC family of proto-oncogenes. It encodes a transcription factor, MYCN, involved in the control of fundamental processes during embryonal development. The MYCN protein is situated downstream of several signaling pathways promoting cell growth, proliferation and metabolism of [...] Read more.
MYCN is a member of the MYC family of proto-oncogenes. It encodes a transcription factor, MYCN, involved in the control of fundamental processes during embryonal development. The MYCN protein is situated downstream of several signaling pathways promoting cell growth, proliferation and metabolism of progenitor cells in different developing organs and tissues. Conversely, deregulated MYCN signaling supports the development of several different tumors, mainly with a childhood onset, including neuroblastoma, medulloblastoma, rhabdomyosarcoma and Wilms’ tumor, but it is also associated with some cancers occurring during adulthood such as prostate and lung cancer. In neuroblastoma, MYCN-amplification is the most consistent genetic aberration associated with poor prognosis and treatment failure. Targeting MYCN has been proposed as a therapeutic strategy for the treatment of these tumors and great efforts have allowed the development of direct and indirect MYCN inhibitors with potential clinical use. Full article
(This article belongs to the Special Issue MYC Networks)
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Open AccessReview
Modeling and Targeting MYC Genes in Childhood Brain Tumors
Received: 2 February 2017 / Revised: 14 March 2017 / Accepted: 16 March 2017 / Published: 23 March 2017
Cited by 8 | PDF Full-text (1626 KB) | HTML Full-text | XML Full-text
Abstract
Brain tumors are the second most common group of childhood cancers, accounting for about 20%–25% of all pediatric tumors. Deregulated expression of the MYC family of transcription factors, particularly c-MYC and MYCN genes, has been found in many of these neoplasms, [...] Read more.
Brain tumors are the second most common group of childhood cancers, accounting for about 20%–25% of all pediatric tumors. Deregulated expression of the MYC family of transcription factors, particularly c-MYC and MYCN genes, has been found in many of these neoplasms, and their expression levels are often correlated with poor prognosis. Elevated c-MYC/MYCN initiates and drives tumorigenesis in many in vivo model systems of pediatric brain tumors. Therefore, inhibition of their oncogenic function is an attractive therapeutic target. In this review, we explore the roles of MYC oncoproteins and their molecular targets during the formation, maintenance, and recurrence of childhood brain tumors. We also briefly summarize recent progress in the development of therapeutic approaches for pharmacological inhibition of MYC activity in these tumors. Full article
(This article belongs to the Special Issue MYC Networks)
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Open AccessReview
MYC in Regulating Immunity: Metabolism and Beyond
Received: 1 January 2017 / Revised: 9 February 2017 / Accepted: 16 February 2017 / Published: 25 February 2017
Cited by 11 | PDF Full-text (1058 KB) | HTML Full-text | XML Full-text
Abstract
Myelocytomatosis oncogene (MYC) family members, including cellular MYC (c-Myc), neuroblastoma derived MYC (MYCN), and lung carcinoma derived MYC (MYCL), have all been implicated as key oncogenic drivers in a broad range of human cancers. Beyond cancer, MYC plays an important role in other [...] Read more.
Myelocytomatosis oncogene (MYC) family members, including cellular MYC (c-Myc), neuroblastoma derived MYC (MYCN), and lung carcinoma derived MYC (MYCL), have all been implicated as key oncogenic drivers in a broad range of human cancers. Beyond cancer, MYC plays an important role in other physiological and pathological processes, namely immunity and immunological diseases. MYC largely functions as a transcription factor that promotes the expression of numerous target genes to coordinate death, proliferation, and metabolism at the cellular, tissue, and organismal levels. It has been shown that the expression of MYC family members is tightly regulated in immune cells during development or upon immune stimulations. Emerging evidence suggests that MYC family members play essential roles in regulating the development, differentiation and activation of immune cells. Through driving the expression of a broad range of metabolic genes in immune cells, MYC family members coordinate metabolic programs to support immune functions. Here, we discuss our understanding of MYC biology in immune system and how modulation of MYC impacts immune metabolism and responses. Full article
(This article belongs to the Special Issue MYC Networks)
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Open AccessReview
MNT and Emerging Concepts of MNT‐MYC Antagonism
Received: 9 January 2017 / Accepted: 16 February 2017 / Published: 20 February 2017
Cited by 5 | PDF Full-text (754 KB) | HTML Full-text | XML Full-text
Abstract
MYC family proteins play fundamental roles in stem and progenitor cell homeostasis, morphogenesis and cancer. As expected for proteins that profoundly affect the fate of cells, the activities of MYC are regulated at a multitude of levels. One mechanism with the potential to [...] Read more.
MYC family proteins play fundamental roles in stem and progenitor cell homeostasis, morphogenesis and cancer. As expected for proteins that profoundly affect the fate of cells, the activities of MYC are regulated at a multitude of levels. One mechanism with the potential to broadly affect the activities of MYC is transcriptional antagonism by a group of MYC‐related transcriptional repressors. From this group, the protein MNT has emerged as having perhaps the most far‐reaching impact on MYC activities. In this review, we discuss the current understanding of MNT, its regulation and how, as a MYC antagonist, it functions both as a tumor suppressor and facilitator of MYC‐driven proliferation and oncogenesis. Full article
(This article belongs to the Special Issue MYC Networks)
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Open AccessReview
Therapeutic Approaches Targeting MYC-Driven Prostate Cancer
Received: 21 December 2016 / Revised: 6 February 2017 / Accepted: 9 February 2017 / Published: 16 February 2017
Cited by 13 | PDF Full-text (703 KB) | HTML Full-text | XML Full-text
Abstract
The transcript encoding the proto-oncogene MYC is commonly overexpressed in prostate cancer (PC). MYC protein abundance is also increased in the majority of cases of advanced and metastatic castrate-resistant PC (mCRPC). Accordingly, the MYC-directed transcriptional program directly contributes to PC by upregulating the [...] Read more.
The transcript encoding the proto-oncogene MYC is commonly overexpressed in prostate cancer (PC). MYC protein abundance is also increased in the majority of cases of advanced and metastatic castrate-resistant PC (mCRPC). Accordingly, the MYC-directed transcriptional program directly contributes to PC by upregulating the expression of a number of pro-tumorigenic factors involved in cell growth and proliferation. A key cellular process downstream of MYC activity is the regulation of ribosome biogenesis which sustains tumor growth. MYC activity also cooperates with the dysregulation of the phosphoinositol-3-kinase (PI3K)/AKT/mTOR pathway to promote PC cell survival. Recent advances in the understanding of these interactions through the use of animal models have provided significant insight into the therapeutic efficacy of targeting MYC activity by interfering with its transcriptional program, and indirectly by targeting downstream cellular events linked to MYC transformation potential. Full article
(This article belongs to the Special Issue MYC Networks)
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