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Myc-Driven Tumorigenesis and Cell Death
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Myc-Driven Tumorigenesis and Cell Death

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

Deadline for manuscript submissions: closed (28 February 2021) | Viewed by 18512

Special Issue Editors

Dr. Eleonora Vecchio

E-Mail Website
Guest Editor
Department of Experimental and Clinical Medicine, University Magna Graecia of Catanzaro, 88100 Catanzaro, Italy
Interests: apoptosis; cell cycle; cell proliferation; cancer-related biochemical pathways; Myc-driven tumorigenesis
Special Issues, Collections and Topics in MDPI journals
Dr. Francesco Albano

E-Mail Website
Guest Editor
1. Institute for Endocrinology and Oncology, National Research Council, 80131 Napoli, Italy
2. Biogem Scarl, 83031 Ariano Irpino, Italy
Interests: apoptosis and cell-survival mechanisms; cell cycle; cell proliferation and differentiation; RNA biology; cancer-related pathways

Special Issue Information

Dear Colleagues,

Myc has a central role in almost every aspect of the oncogenic process, orchestrating proliferation, apoptosis, differentiation, and metabolism. The Myc family oncogene is deregulated in >50% of human cancers, and this deregulation is frequently associated with poor prognosis and unfavorable patient survival. Notably, Myc is frequently overexpressed in hematological malignancies due to gene amplification or translocation. Apoptosis is the main mechanism that counteracts cell proliferation driven by oncogenes, thus limiting cancer development. Myc is a unique oncogene which, alone, can potently induce cell death and carcinogenesis in transgenic animals. Of note, in an Emu-myc transgenic mouse model of B-lymphomagenesis, the pre-cancerous state is characterized by aberrant proliferation of B-lymphoid cells, which is initially offset by pro-apoptotic action of Myc. The resistance of pre-cancerous B cells to Myc-induced apoptosis must occur to proceed toward malignancy. Both basic and translational cancer research have greatly benefited from the use of suitable cellular and animal models, which have helped to characterise the molecular basis of Myc-driven cancers.

We invite investigators to contribute original research articles and review articles describing and discussing the molecular mechanisms at the basis of cooperative Myc-driven tumourigenesis, using basic and translational experimental models.

Dr. Eleonora Vecchio
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.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Myc and cancer initiation
  • Myc and cancer cell death
  • Non Hodkin’s lymphoma and other hematological malignancies
  • Myc and drug discovery
  • targeting Myc and RAS driven cancer
  • transgenic mouse model

Published Papers (5 papers)

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Research

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14 pages, 3553 KiB  
Communication
IBtkα Activates the β-Catenin-Dependent Transcription of MYC through Ubiquitylation and Proteasomal Degradation of GSK3β in Cancerous B Cells
by Eleonora Vecchio, Nancy Nisticò, Gaetanina Golino, Enrico Iaccino, Domenico Maisano, Selena Mimmi, Annamaria Aloisio, Maurizio Renna, Angelica Avagliano, Alessandro Arcucci, Giuseppe Fiume and Ileana Quinto
Int. J. Mol. Sci. 2022, 23(4), 2044; https://doi.org/10.3390/ijms23042044 - 12 Feb 2022
Cited by 6 | Viewed by 1769
Abstract
The IBTK gene encodes the IBtkα protein that is a substrate receptor of E3 ubiquitin ligase, Cullin 3. We have previously reported the pro-tumorigenic activity of Ibtk in MYC-dependent B-lymphomagenesis observed in Eμ-myc transgenic mice. Here, we provide mechanistic evidence of the [...] Read more.
The IBTK gene encodes the IBtkα protein that is a substrate receptor of E3 ubiquitin ligase, Cullin 3. We have previously reported the pro-tumorigenic activity of Ibtk in MYC-dependent B-lymphomagenesis observed in Eμ-myc transgenic mice. Here, we provide mechanistic evidence of the functional interplay between IBtkα and MYC. We show that IBtkα, albeit indirectly, activates the β-catenin-dependent transcription of the MYC gene. Of course, IBtkα associates with GSK3β and promotes its ubiquitylation, which is associated with proteasomal degradation. This event increases the protein level of β-catenin, a substrate of GSK3β, and results in the transcriptional activation of the MYC and CCND1 target genes of β-catenin, which are involved in the control of cell division and apoptosis. In particular, we found that in Burkitt’s lymphoma cells, IBtkα silencing triggered the downregulation of both MYC mRNA and protein expression, as well as a strong decrease of cell survival, mainly through the induction of apoptotic events, as assessed by using flow cytometry-based cell cycle and apoptosis analysis. Collectively, our results shed further light on the complex puzzle of IBtkα interactome and highlight IBtkα as a potential novel therapeutic target to be employed in the strategy for personalized therapy of B cell lymphoma. Full article
(This article belongs to the Special Issue Myc-Driven Tumorigenesis and Cell Death)
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22 pages, 5010 KiB  
Article
Pivotal Role of Fatty Acid Synthase in c-MYC Driven Hepatocarcinogenesis
by Jiaoyuan Jia, Li Che, Antonio Cigliano, Xue Wang, Graziella Peitta, Junyan Tao, Sheng Zhong, Silvia Ribback, Matthias Evert, Xin Chen and Diego F. Calvisi
Int. J. Mol. Sci. 2020, 21(22), 8467; https://doi.org/10.3390/ijms21228467 - 11 Nov 2020
Cited by 20 | Viewed by 3194
Abstract
Hepatocellular carcinoma (HCC) is a deadly form of liver malignancy with limited treatment options. Amplification and/or overexpression of c-MYC is one of the most frequent genetic events in human HCC. The mammalian target of Rapamycin Complex 1 (mTORC1) is a major functional axis [...] Read more.
Hepatocellular carcinoma (HCC) is a deadly form of liver malignancy with limited treatment options. Amplification and/or overexpression of c-MYC is one of the most frequent genetic events in human HCC. The mammalian target of Rapamycin Complex 1 (mTORC1) is a major functional axis regulating various aspects of cellular growth and metabolism. Recently, we demonstrated that mTORC1 is necessary for c-Myc driven hepatocarcinogenesis as well as for HCC cell growth in vitro. Among the pivotal downstream effectors of mTORC1, upregulation of Fatty Acid Synthase (FASN) and its mediated de novo lipogenesis is a hallmark of human HCC. Here, we investigated the importance of FASN on c-Myc-dependent hepatocarcinogenesis using in vitro and in vivo approaches. In mouse and human HCC cells, we found that FASN suppression by either gene silencing or soluble inhibitors more effectively suppressed proliferation and induced apoptosis in the presence of high c-MYC expression. In c-Myc/Myeloid cell leukemia 1 (MCL1) mouse liver tumor lesions, FASN expression was markedly upregulated. Most importantly, genetic ablation of Fasn profoundly delayed (without abolishing) c-Myc/MCL1 induced HCC formation. Liver tumors developing in c-Myc/MCL1 mice depleted of Fasn showed a reduction in proliferation and an increase in apoptosis when compared with corresponding lesions from c-Myc/MCL1 mice with an intact Fasn gene. In human HCC samples, a significant correlation between the levels of c-MYC transcriptional activity and the expression of FASN mRNA was detected. Altogether, our study indicates that FASN is an important effector downstream of mTORC1 in c-MYC induced HCC. Targeting FASN may be helpful for the treatment of human HCC, at least in the tumor subset displaying c-MYC amplification or activation. Full article
(This article belongs to the Special Issue Myc-Driven Tumorigenesis and Cell Death)
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Review

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20 pages, 2008 KiB  
Review
The Contribution of Autophagy and LncRNAs to MYC-Driven Gene Regulatory Networks in Cancers
by Leila Jahangiri, Perla Pucci, Tala Ishola, Ricky M. Trigg, John A. Williams, Joao Pereira, Megan L. Cavanagh, Suzanne D. Turner, Georgios V. Gkoutos and Loukia Tsaprouni
Int. J. Mol. Sci. 2021, 22(16), 8527; https://doi.org/10.3390/ijms22168527 - 08 Aug 2021
Cited by 10 | Viewed by 4231
Abstract
MYC is a target of the Wnt signalling pathway and governs numerous cellular and developmental programmes hijacked in cancers. The amplification of MYC is a frequently occurring genetic alteration in cancer genomes, and this transcription factor is implicated in metabolic reprogramming, cell death, [...] Read more.
MYC is a target of the Wnt signalling pathway and governs numerous cellular and developmental programmes hijacked in cancers. The amplification of MYC is a frequently occurring genetic alteration in cancer genomes, and this transcription factor is implicated in metabolic reprogramming, cell death, and angiogenesis in cancers. In this review, we analyse MYC gene networks in solid cancers. We investigate the interaction of MYC with long non-coding RNAs (lncRNAs). Furthermore, we investigate the role of MYC regulatory networks in inducing changes to cellular processes, including autophagy and mitophagy. Finally, we review the interaction and mutual regulation between MYC and lncRNAs, and autophagic processes and analyse these networks as unexplored areas of targeting and manipulation for therapeutic gain in MYC-driven malignancies. Full article
(This article belongs to the Special Issue Myc-Driven Tumorigenesis and Cell Death)
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28 pages, 2567 KiB  
Review
The Molecular ‘Myc-anisms’ behind Myc-Driven Tumorigenesis and the Relevant Myc-Directed Therapeutics
by Jessica McAnulty and Analisa DiFeo
Int. J. Mol. Sci. 2020, 21(24), 9486; https://doi.org/10.3390/ijms21249486 - 13 Dec 2020
Cited by 15 | Viewed by 5186
Abstract
MYC, a well-studied proto-oncogene that is overexpressed in >20% of tumors across all cancers, is classically known as “undruggable” due to its crucial roles in cell processes and its lack of a drug binding pocket. Four decades of research and creativity led [...] Read more.
MYC, a well-studied proto-oncogene that is overexpressed in >20% of tumors across all cancers, is classically known as “undruggable” due to its crucial roles in cell processes and its lack of a drug binding pocket. Four decades of research and creativity led to the discovery of a myriad of indirect (and now some direct!) therapeutic strategies targeting Myc. This review explores the various mechanisms in which Myc promotes cancer and highlights five key therapeutic approaches to disrupt Myc, including transcription, Myc-Max dimerization, protein stability, cell cycle regulation, and metabolism, in order to develop more specific Myc-directed therapies. Full article
(This article belongs to the Special Issue Myc-Driven Tumorigenesis and Cell Death)
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14 pages, 679 KiB  
Review
Insights about MYC and Apoptosis in B-Lymphomagenesis: An Update from Murine Models
by Eleonora Vecchio, Giuseppe Fiume, Serena Correnti, Salvatore Romano, Enrico Iaccino, Selena Mimmi, Domenico Maisano, Nancy Nisticò and Ileana Quinto
Int. J. Mol. Sci. 2020, 21(12), 4265; https://doi.org/10.3390/ijms21124265 - 15 Jun 2020
Cited by 12 | Viewed by 3376
Abstract
The balance between cell survival and cell death represents an essential part of human tissue homeostasis, while altered apoptosis contributes to several pathologies and can affect the treatment efficacy. Impaired apoptosis is one of the main cancer hallmarks and some types of lymphomas [...] Read more.
The balance between cell survival and cell death represents an essential part of human tissue homeostasis, while altered apoptosis contributes to several pathologies and can affect the treatment efficacy. Impaired apoptosis is one of the main cancer hallmarks and some types of lymphomas harbor mutations that directly affect key regulators of cell death (such as BCL-2 family members). The development of novel techniques in the field of immunology and new animal models has greatly accelerated our understanding of oncogenic mechanisms in MYC-associated lymphomas. Mouse models are a powerful tool to reveal multiple genes implicated in the genesis of lymphoma and are extensively used to clarify the molecular mechanism of lymphoma, validating the gene function. Key features of MYC-induced apoptosis will be discussed here along with more recent studies on MYC direct and indirect interactors, including their cooperative action in lymphomagenesis. We review our current knowledge about the role of MYC-induced apoptosis in B-cell malignancies, discussing the transcriptional regulation network of MYC and regulatory feedback action of miRs during MYC-driven lymphomagenesis. More importantly, the finding of new modulators of apoptosis now enabling researchers to translate the discoveries that have been made in the laboratory into clinical practice to positively impact human health. Full article
(This article belongs to the Special Issue Myc-Driven Tumorigenesis and Cell Death)
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