The “Superoncogene” Myc at the Crossroad between Metabolism and Gene Expression in Glioblastoma Multiforme

Cencioni, Chiara; Scagnoli, Fiorella; Spallotta, Francesco; Nasi, Sergio; Illi, Barbara

doi:10.3390/ijms24044217

Cited by 10 publications

(7 citation statements)

References 330 publications

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“…In fact, c-MYC is overexpressed and drives tumorigenesis in more than 40% of human tumors [ 17 ]. Additionally, c-MYC is recognized as a key regulator of stemness and is associated with the regulation of various stem cell properties [ 22 ]. Previous studies have demonstrated the significant role of c-MYC in controlling the self-renewal, survival, and stemness transformation of GSCs [ 21 ].…”

Section: Discussionmentioning

confidence: 99%

“…At the transcriptional level, it is responsible for the upregulation of epidermal growth factor receptor (EGFR). And it participates in the expression or transcriptional inhibition of various microRNAs involved in chemotherapy resistance [ 22 ]. Some of MYC’s oncogenic effects are exerted through its molecular partners within the protein network.…”

Section: Introductionmentioning

confidence: 99%

“…Notably, c-MYC represents one of the critical genes governing the stem cell properties of GSCs [ 23 ]. Inhibition of c-MYC results in a profound reset of transcriptional nodes in GSCs, parallel to changes in their biological characteristics [ 22 ]. Despite the significant role of c-MYC in tumorigenesis, direct targeting of c-MYC in clinical settings is considered impractical due to its substantial side effects [ 24 ].…”

Section: Introductionmentioning

confidence: 99%

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The promoting effect and mechanism of MAD2L2 on stemness maintenance and malignant progression in glioma

Liu,

Wang,

et al. 2023

J Transl Med

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Background Glioblastoma, the most common primary malignant tumor of the brain, is associated with poor prognosis. Glioblastoma cells exhibit high proliferative and invasive properties, and glioblastoma stem cells (GSCs) have been shown to play a crucial role in the malignant behavior of glioblastoma cells. This study aims to investigate the molecular mechanisms involved in GSCs maintenance and malignant progression. Methods Bioinformatics analysis was performed based on data from public databases to explore the expression profile of Mitotic arrest deficient 2 like 2 (MAD2L2) and its potential function in glioma. The impact of MAD2L2 on glioblastoma cell behaviors was assessed through cell viability assays (CCK8), colony formation assays, 5-Ethynyl-2ʹ-deoxyuridine (EDU) incorporation assays, scratch assays, and transwell migration/invasion assays. The findings from in vitro experiments were further validated in vivo using xenograft tumor model. GSCs were isolated from the U87 and LN229 cell lines through flow cytometry and the stemness characteristics were verified by immunofluorescence staining. The sphere-forming ability of GSCs was examined using the stem cell sphere formation assay. Bioinformatics methods were conducted to identified the potential downstream target genes of MAD2L2, followed by in vitro experimental validation. Furthermore, potential upstream transcription factors that regulate MAD2L2 expression were confirmed through chromatin immunoprecipitation (ChIP) and dual-luciferase reporter assays. Results The MAD2L2 exhibited high expression in glioblastoma samples and showed significant correlation with patient prognosis. In vitro and in vivo experiments confirmed that silencing of MAD2L2 led to decreased proliferation, invasion, and migration capabilities of glioblastoma cells, while decreasing stemness characteristics of glioblastoma stem cells. Conversely, overexpression of MAD2L2 enhanced these malignant behaviors. Further investigation revealed that MYC proto-oncogene (c-MYC) mediated the functional role of MAD2L2 in glioblastoma, which was further validated through a rescue experiment. Moreover, using dual-luciferase reporter gene assays and ChIP assays determined that the upstream transcription factor E2F-1 regulated the expression of MAD2L2. Conclusion Our study elucidated the role of MAD2L2 in maintaining glioblastoma stemness and promoting malignant behaviors through the regulation of c-MYC, suggesting its potential as a therapeutic target.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The promoting effect and mechanism of MAD2L2 on stemness maintenance and malignant progression in glioma

Liu,

Wang,

et al. 2023

J Transl Med

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“…As for the cell cycle, Myc also controls ES metabolism, which mainly depends on aerobic glycolysis [ 89 ], also known as the Warburg effect, a phenomenon extensively investigated in cancer cells [ 90 ]. Myc basically regulates any metabolic pathway, from glycolysis and glutaminolysis to nucleotides, ‘lipids’ and amino acids’ synthesis [ 91 , 92 ]. It has been demonstrated that, upon mir290-mediated derepression, Myc directly binds the promoters of pyruvate kinase M2 ( PKM2) and lactate dehydrogenase A (LDHA) genes, allowing the glycolytic metabolic switch in ES [ 93 ].…”

Section: The Role Of Myc In Pluripotent Stem Cellsmentioning

confidence: 99%

Myc beyond Cancer: Regulation of Mammalian Tissue Regeneration

Illi

Nasi

2023

Pathophysiology

Self Cite

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Myc is one of the most well-known oncogenes driving tumorigenesis in a wide variety of tissues. From the brain to blood, its deregulation derails physiological pathways that grant the correct functioning of the cell. Its action is carried out at the gene expression level, where Myc governs basically every aspect of transcription. Indeed, in addition to its role as a canonical, chromatin-bound transcription factor, Myc rules RNA polymerase II (RNAPII) transcriptional pause–release, elongation and termination and mRNA capping. For this reason, it is evident that minimal perturbations of Myc function mirror malignant cell behavior and, consistently, a large body of literature mainly focuses on Myc malfunctioning. In healthy cells, Myc controls molecular mechanisms involved in pivotal functions, such as cell cycle (and proliferation thereof), apoptosis, metabolism and cell size, angiogenesis, differentiation and stem cell self-renewal. In this latter regard, Myc has been found to also regulate tissue regeneration, a hot topic in the research fields of aging and regenerative medicine. Indeed, Myc appears to have a role in wound healing, in peripheral nerves and in liver, pancreas and even heart recovery. Herein, we discuss the state of the art of Myc’s role in tissue regeneration, giving an overview of its potent action beyond cancer.

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“…MYC is a transcription factor that belongs to the basic helix-loop-helix-leucine zipper (bHLHZip) family and regulates cell growth, differentiation, metabolism, and cell death. Thus, MYC functions as a master regulator of major cellular functions [75][76][77][78]. Studies using knockout mice have shown that MYC is particularly important for cell growth (accumulation of the body mass) and is indispensable during the period of both embryogenesis and adulthood [79].…”

Section: Myc: a Master Regulator Of Cellular Activitymentioning

confidence: 99%

Interaction and Collaboration of SP1, HIF-1, and MYC in Regulating the Expression of Cancer-Related Genes to Further Enhance Anticancer Drug Development

Kimura,

Jackson,

Huang

2023

CIMB

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Specificity protein 1 (SP1), hypoxia-inducible factor 1 (HIF-1), and MYC are important transcription factors (TFs). SP1, a constitutively expressed housekeeping gene, regulates diverse yet distinct biological activities; MYC is a master regulator of all key cellular activities including cell metabolism and proliferation; and HIF-1, whose protein level is rapidly increased when the local tissue oxygen concentration decreases, functions as a mediator of hypoxic signals. Systems analyses of the regulatory networks in cancer have shown that SP1, HIF-1, and MYC belong to a group of TFs that function as master regulators of cancer. Therefore, the contributions of these TFs are crucial to the development of cancer. SP1, HIF-1, and MYC are often overexpressed in tumors, which indicates the importance of their roles in the development of cancer. Thus, proper manipulation of SP1, HIF-1, and MYC by appropriate agents could have a strong negative impact on cancer development. Under these circumstances, these TFs have naturally become major targets for anticancer drug development. Accordingly, there are currently many SP1 or HIF-1 inhibitors available; however, designing efficient MYC inhibitors has been extremely difficult. Studies have shown that SP1, HIF-1, and MYC modulate the expression of each other and collaborate to regulate the expression of numerous genes. In this review, we provide an overview of the interactions and collaborations of SP1, HIF1A, and MYC in the regulation of various cancer-related genes, and their potential implications in the development of anticancer therapy.

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The “Superoncogene” Myc at the Crossroad between Metabolism and Gene Expression in Glioblastoma Multiforme

Cited by 10 publications

References 330 publications

The promoting effect and mechanism of MAD2L2 on stemness maintenance and malignant progression in glioma

The promoting effect and mechanism of MAD2L2 on stemness maintenance and malignant progression in glioma

Myc beyond Cancer: Regulation of Mammalian Tissue Regeneration

Interaction and Collaboration of SP1, HIF-1, and MYC in Regulating the Expression of Cancer-Related Genes to Further Enhance Anticancer Drug Development

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