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Myc Function and Regulation

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Biology".

Deadline for manuscript submissions: closed (20 September 2020) | Viewed by 49688

Special Issue Editors

1. Laboratory of Metabolism of Cell Growth and Neuronal Survival, Department of Cellular, Computational and Integrative Biology, University of Trento, Trento, Italy
2. Department of Medicine & Endocrinology, NYU Langone Medical Center, Smilow Research Building, 550 First Ave, New York, NY 10016, USA
Interests: Myc; growth; ribosomal biogenesis; autophagy; insulin/TOR signaling; lipid metabolism; neuronal degeneration; Huntington’s disease
Special Issues, Collections and Topics in MDPI journals
Department of Cellular, Computational and Integrative Biology-CIBIO University of Trento, Via Sommarive, 9I-38123 Povo, Trento, Italy
Interests: transcription regulation; chemoresistance; cancer stem cells; epithelial-to-mesenchymal transition; breast cancer

Special Issue Information

Dear Colleagues,

Although more than 25 years have passed since the discovery of Myc, and over 34,000 publications have been written, what do we know about the function of this fundamental gene? This Special Issue will try to provide an overview of the work of many scientists who have helped to understand the physiological function of Myc, from its role in the control of animal development and organ growth, to its ability to rewire and control cellular metabolic pathways to drive the growth of tumors.

Prof. Dr. Paola Bellosta
Dr. Yari Ciribilli
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

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Keywords

  • organ growth
  • cell competition
  • development/evolution
  • ribosome biogenesis
  • stem cell/regeneration
  • chromatin modification
  • epigenetics
  • cancer metabolism
  • leukemia and others tumors

Published Papers (9 papers)

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Research

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19 pages, 2211 KiB  
Article
Dual-Inhibitors of N-Myc and AURKA as Potential Therapy for Neuroendocrine Prostate Cancer
by Anh-Tien Ton, Kriti Singh, Hélène Morin, Fuqiang Ban, Eric Leblanc, Joseph Lee, Nada Lallous and Artem Cherkasov
Int. J. Mol. Sci. 2020, 21(21), 8277; https://doi.org/10.3390/ijms21218277 - 05 Nov 2020
Cited by 13 | Viewed by 2786
Abstract
Resistance to androgen-receptor (AR) directed therapies is, among other factors, associated with Myc transcription factors that are involved in development and progression of many cancers. Overexpression of N-Myc protein in prostate cancer (PCa) leads to its transformation to advanced neuroendocrine prostate cancer (NEPC) [...] Read more.
Resistance to androgen-receptor (AR) directed therapies is, among other factors, associated with Myc transcription factors that are involved in development and progression of many cancers. Overexpression of N-Myc protein in prostate cancer (PCa) leads to its transformation to advanced neuroendocrine prostate cancer (NEPC) that currently has no approved treatments. N-Myc has a short half-life but acts as an NEPC stimulator when it is stabilized by forming a protective complex with Aurora A kinase (AURKA). Therefore, dual-inhibition of N-Myc and AURKA would be an attractive therapeutic avenue for NEPC. Following our computer-aided drug discovery approach, compounds exhibiting potent N-Myc specific inhibition and strong anti-proliferative activity against several N-Myc driven cell lines, were identified. Thereafter, we have developed dual inhibitors of N-Myc and AURKA through structure-based drug design approach by merging our novel N-Myc specific chemical scaffolds with fragments of known AURKA inhibitors. Favorable binding modes of the designed compounds to both N-Myc and AURKA target sites have been predicted by docking. A promising lead compound, 70812, demonstrated low-micromolar potency against both N-Myc and AURKA in vitro assays and effectively suppressed NEPC cell growth. Full article
(This article belongs to the Special Issue Myc Function and Regulation)
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12 pages, 2749 KiB  
Article
High MYC mRNA Expression Is More Clinically Relevant than MYC DNA Amplification in Triple-Negative Breast Cancer
by Eriko Katsuta, Li Yan, Takashi Takeshita, Kerry-Ann McDonald, Subhamoy Dasgupta, Mateusz Opyrchal and Kazuaki Takabe
Int. J. Mol. Sci. 2020, 21(1), 217; https://doi.org/10.3390/ijms21010217 - 28 Dec 2019
Cited by 34 | Viewed by 4529
Abstract
DNA abnormalities are used in inclusion criteria of clinical trials for treatments with specific targeted molecules. MYC is one of the most powerful oncogenes and is known to be associated with triple-negative breast cancer (TNBC). Its DNA amplification is often part of the [...] Read more.
DNA abnormalities are used in inclusion criteria of clinical trials for treatments with specific targeted molecules. MYC is one of the most powerful oncogenes and is known to be associated with triple-negative breast cancer (TNBC). Its DNA amplification is often part of the targeted DNA-sequencing panels under the assumption of reflecting upregulated signaling. However, it remains unclear if MYC DNA amplification is a surrogate of its upregulated signaling. Thus, we investigated the difference between MYC DNA amplification and mRNA high expression in TNBCs utilizing publicly available cohorts. MYC DNA amplified tumors were found to have various mRNA expression levels, suggesting that MYC DNA amplification does not always result in elevated MYC mRNA expression. Compared to other subtypes, both MYC DNA amplification and mRNA high expression were more frequent in the TNBCs. MYC mRNA high expression, but not DNA amplification, was significantly associated with worse overall survival in the TNBCs. The TNBCs with MYC mRNA high expression enriched MYC target genes, cell cycle related genes, and WNT/β-catenin gene sets, whereas none of them were enriched in MYC DNA amplified TNBCs. In conclusion, MYC mRNA high expression, but not DNA amplification, reflects not only its upregulated signaling pathway, but also clinical significance in TNBCs. Full article
(This article belongs to the Special Issue Myc Function and Regulation)
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Review

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22 pages, 1239 KiB  
Review
MYC Ran Up the Clock: The Complex Interplay between MYC and the Molecular Circadian Clock in Cancer
by Jamison B. Burchett, Amelia M. Knudsen-Clark and Brian J. Altman
Int. J. Mol. Sci. 2021, 22(14), 7761; https://doi.org/10.3390/ijms22147761 - 20 Jul 2021
Cited by 13 | Viewed by 3793
Abstract
The MYC oncoprotein and its family members N-MYC and L-MYC are known to drive a wide variety of human cancers. Emerging evidence suggests that MYC has a bi-directional relationship with the molecular clock in cancer. The molecular clock is responsible for circadian (~24 [...] Read more.
The MYC oncoprotein and its family members N-MYC and L-MYC are known to drive a wide variety of human cancers. Emerging evidence suggests that MYC has a bi-directional relationship with the molecular clock in cancer. The molecular clock is responsible for circadian (~24 h) rhythms in most eukaryotic cells and organisms, as a mechanism to adapt to light/dark cycles. Disruption of human circadian rhythms, such as through shift work, may serve as a risk factor for cancer, but connections with oncogenic drivers such as MYC were previously not well understood. In this review, we examine recent evidence that MYC in cancer cells can disrupt the molecular clock; and conversely, that molecular clock disruption in cancer can deregulate and elevate MYC. Since MYC and the molecular clock control many of the same processes, we then consider competition between MYC and the molecular clock in several select aspects of tumor biology, including chromatin state, global transcriptional profile, metabolic rewiring, and immune infiltrate in the tumor. Finally, we discuss how the molecular clock can be monitored or diagnosed in human tumors, and how MYC inhibition could potentially restore molecular clock function. Further study of the relationship between the molecular clock and MYC in cancer may reveal previously unsuspected vulnerabilities which could lead to new treatment strategies. Full article
(This article belongs to the Special Issue Myc Function and Regulation)
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18 pages, 1120 KiB  
Review
MYC-Induced Replicative Stress: A Double-Edged Sword for Cancer Development and Treatment
by Laura Curti and Stefano Campaner
Int. J. Mol. Sci. 2021, 22(12), 6168; https://doi.org/10.3390/ijms22126168 - 08 Jun 2021
Cited by 17 | Viewed by 2683
Abstract
MYC is a transcription factor that controls the expression of a large fraction of cellular genes linked to cell cycle progression, metabolism and differentiation. MYC deregulation in tumors leads to its pervasive genome-wide binding of both promoters and distal regulatory regions, associated with [...] Read more.
MYC is a transcription factor that controls the expression of a large fraction of cellular genes linked to cell cycle progression, metabolism and differentiation. MYC deregulation in tumors leads to its pervasive genome-wide binding of both promoters and distal regulatory regions, associated with selective transcriptional control of a large fraction of cellular genes. This pairs with alterations of cell cycle control which drive anticipated S-phase entry and reshape the DNA-replication landscape. Under these circumstances, the fine tuning of DNA replication and transcription becomes critical and may pose an intrinsic liability in MYC-overexpressing cancer cells. Here, we will review the current understanding of how MYC controls DNA and RNA synthesis, discuss evidence of replicative and transcriptional stress induced by MYC and summarize preclinical data supporting the therapeutic potential of triggering replicative stress in MYC-driven tumors. Full article
(This article belongs to the Special Issue Myc Function and Regulation)
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14 pages, 1313 KiB  
Review
MYC in Brain Development and Cancer
by Olga Zaytseva, Nan-hee Kim and Leonie M. Quinn
Int. J. Mol. Sci. 2020, 21(20), 7742; https://doi.org/10.3390/ijms21207742 - 20 Oct 2020
Cited by 17 | Viewed by 3155
Abstract
The MYC family of transcriptional regulators play significant roles in animal development, including the renewal and maintenance of stem cells. Not surprisingly, given MYC’s capacity to promote programs of proliferative cell growth, MYC is frequently upregulated in cancer. Although members of the MYC [...] Read more.
The MYC family of transcriptional regulators play significant roles in animal development, including the renewal and maintenance of stem cells. Not surprisingly, given MYC’s capacity to promote programs of proliferative cell growth, MYC is frequently upregulated in cancer. Although members of the MYC family are upregulated in nervous system tumours, the mechanisms of how elevated MYC promotes stem cell-driven brain cancers is unknown. If we are to determine how increased MYC might contribute to brain cancer progression, we will require a more complete understanding of MYC’s roles during normal brain development. Here, we evaluate evidence for MYC family functions in neural stem cell fate and brain development, with a view to better understand mechanisms of MYC-driven neural malignancies. Full article
(This article belongs to the Special Issue Myc Function and Regulation)
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29 pages, 1632 KiB  
Review
MYC as a Multifaceted Regulator of Tumor Microenvironment Leading to Metastasis
by Erna Marija Meškytė, Sabiha Keskas and Yari Ciribilli
Int. J. Mol. Sci. 2020, 21(20), 7710; https://doi.org/10.3390/ijms21207710 - 18 Oct 2020
Cited by 50 | Viewed by 4910
Abstract
The Myc family of oncogenes is deregulated in many types of cancer, and their over-expression is often correlated with poor prognosis. The Myc family members are transcription factors that can coordinate the expression of thousands of genes. Among them, c-Myc (MYC) is the [...] Read more.
The Myc family of oncogenes is deregulated in many types of cancer, and their over-expression is often correlated with poor prognosis. The Myc family members are transcription factors that can coordinate the expression of thousands of genes. Among them, c-Myc (MYC) is the gene most strongly associated with cancer, and it is the focus of this review. It regulates the expression of genes involved in cell proliferation, growth, differentiation, self-renewal, survival, metabolism, protein synthesis, and apoptosis. More recently, novel studies have shown that MYC plays a role not only in tumor initiation and growth but also has a broader spectrum of functions in tumor progression. MYC contributes to angiogenesis, immune evasion, invasion, and migration, which all lead to distant metastasis. Moreover, MYC is able to promote tumor growth and aggressiveness by recruiting stromal and tumor-infiltrating cells. In this review, we will dissect all of these novel functions and their involvement in the crosstalk between tumor and host, which have demonstrated that MYC is undoubtedly the master regulator of the tumor microenvironment. In sum, a better understanding of MYC’s role in the tumor microenvironment and metastasis development is crucial in proposing novel and effective cancer treatment strategies. Full article
(This article belongs to the Special Issue Myc Function and Regulation)
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19 pages, 1600 KiB  
Review
Myc as a Regulator of Ribosome Biogenesis and Cell Competition: A Link to Cancer
by Francesca Destefanis, Valeria Manara and Paola Bellosta
Int. J. Mol. Sci. 2020, 21(11), 4037; https://doi.org/10.3390/ijms21114037 - 05 Jun 2020
Cited by 31 | Viewed by 9018
Abstract
The biogenesis of ribosomes is a finely regulated multistep process linked to cell proliferation and growth—processes which require a high rate of protein synthesis. One of the master regulators of ribosome biogenesis is Myc, a well-known proto-oncogene that has an important role in [...] Read more.
The biogenesis of ribosomes is a finely regulated multistep process linked to cell proliferation and growth—processes which require a high rate of protein synthesis. One of the master regulators of ribosome biogenesis is Myc, a well-known proto-oncogene that has an important role in ribosomal function and in the regulation of protein synthesis. The relationship between Myc and the ribosomes was first highlighted in Drosophila, where Myc’s role in controlling Pol-I, II and III was evidenced by both microarrays data, and by the ability of Myc to control growth (mass), and cellular and animal size. Moreover, Myc can induce cell competition, a physiological mechanism through which cells with greater fitness grow better and thereby prevail over less competitive cells, which are actively eliminated by apoptosis. Myc-induced cell competition was shown to regulate both vertebrate development and tumor promotion; however, how these functions are linked to Myc’s control of ribosome biogenesis, protein synthesis and growth is not clear yet. In this review, we will discuss the major pathways that link Myc to ribosomal biogenesis, also in light of its function in cell competition, and how these mechanisms may reflect its role in favoring tumor promotion. Full article
(This article belongs to the Special Issue Myc Function and Regulation)
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18 pages, 1366 KiB  
Review
The Complex Network between MYC Oncogene and microRNAs in Gastric Cancer: An Overview
by Ana Carolina Anauate, Mariana Ferreira Leal, Danielle Queiroz Calcagno, Carolina Oliveira Gigek, Bruno Takao Real Karia, Fernanda Wisnieski, Leonardo Caires dos Santos, Elizabeth Suchi Chen, Rommel Rodríguez Burbano and Marília Arruda Cardoso Smith
Int. J. Mol. Sci. 2020, 21(5), 1782; https://doi.org/10.3390/ijms21051782 - 05 Mar 2020
Cited by 12 | Viewed by 3659
Abstract
Despite the advancements in cancer treatments, gastric cancer is still one of the leading causes of death worldwide. In this context, it is of great interest to discover new and more effective ways of treating this disease. Accumulated evidences have demonstrated the amplification [...] Read more.
Despite the advancements in cancer treatments, gastric cancer is still one of the leading causes of death worldwide. In this context, it is of great interest to discover new and more effective ways of treating this disease. Accumulated evidences have demonstrated the amplification of 8q24.21 region in gastric tumors. Furthermore, this is the region where the widely known MYC oncogene and different microRNAs are located. MYC deregulation is key in tumorigenesis in various types of tissues, once it is associated with cell proliferation, survival, and drug resistance. microRNAs are a class of noncoding RNAs that negatively regulate the protein translation, and which deregulation is related with gastric cancer development. However, little is understood about the interactions between microRNAs and MYC. Here, we overview the MYC role and its relationship with the microRNAs network in gastric cancer aiming to identify potential targets useful to be used in clinic, not only as biomarkers, but also as molecules for development of promising therapies. Full article
(This article belongs to the Special Issue Myc Function and Regulation)
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16 pages, 2230 KiB  
Review
Emerging Roles of C-Myc in Cancer Stem Cell-Related Signaling and Resistance to Cancer Chemotherapy: A Potential Therapeutic Target Against Colorectal Cancer
by Mohamed Elbadawy, Tatsuya Usui, Hideyuki Yamawaki and Kazuaki Sasaki
Int. J. Mol. Sci. 2019, 20(9), 2340; https://doi.org/10.3390/ijms20092340 - 11 May 2019
Cited by 161 | Viewed by 14241
Abstract
Myc is a nuclear transcription factor that mainly regulates cell growth, cell cycle, metabolism, and survival. Myc family proteins contain c-Myc, n-Myc, and l-Myc. Among them, c-Myc can become a promising therapeutic target molecule in cancer. Cancer stem cells (CSCs) are known to [...] Read more.
Myc is a nuclear transcription factor that mainly regulates cell growth, cell cycle, metabolism, and survival. Myc family proteins contain c-Myc, n-Myc, and l-Myc. Among them, c-Myc can become a promising therapeutic target molecule in cancer. Cancer stem cells (CSCs) are known to be responsible for the therapeutic resistance. In the previous study, we demonstrated that c-Myc mediates drug resistance of colorectal CSCs using a patient-derived primary three-dimensional (3D) organoid culture. In this review, we mainly focus on the roles of c-Myc-related signaling in the regulation of CSCs, chemotherapy resistance, and colorectal cancer organoids. Finally, we introduce the various types of c-Myc inhibitors and propose the possibility of c-Myc as a therapeutic target against colorectal cancer. Full article
(This article belongs to the Special Issue Myc Function and Regulation)
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