-
The EMBO Journal Dec 2017Transcription factors of the MYC family are deregulated in the majority of all human cancers. Oncogenic levels of MYC reprogram cellular metabolism, a hallmark of cancer... (Review)
Review
Transcription factors of the MYC family are deregulated in the majority of all human cancers. Oncogenic levels of MYC reprogram cellular metabolism, a hallmark of cancer development, to sustain the high rate of proliferation of cancer cells. Conversely, cells need to modulate MYC function according to the availability of nutrients, in order to avoid a metabolic collapse. Here, we review recent evidence that the multiple interactions of MYC with cell metabolism are mutual and review mechanisms that control MYC levels and function in response to metabolic stress situations. The main hypothesis we put forward is that regulation of MYC levels is an integral part of the adaptation of cells to nutrient deprivation. Since such mechanisms would be particularly relevant in tumor cells, we propose that-in contrast to growth factor-dependent controls-they are not disrupted during tumorigenesis and that maintaining flexibility of expression is integral to MYC's oncogenic function.
Topics: Animals; Apoptosis; Biogenic Polyamines; Forkhead Box Protein O1; Genes, myc; Glucose; Glutamine; Humans; Mechanistic Target of Rapamycin Complex 1; Metabolic Networks and Pathways; Neoplasms; Nucleotides; Proto-Oncogene Proteins c-myc; Stress, Physiological
PubMed: 29127156
DOI: 10.15252/embj.201796438 -
Methods in Molecular Biology (Clifton,... 2021The MYC gene regulates normal cell growth and is deregulated in many human cancers, contributing to tumor growth and progression. The MYC transcription factor activates...
The MYC gene regulates normal cell growth and is deregulated in many human cancers, contributing to tumor growth and progression. The MYC transcription factor activates RNA polymerases I, II, and III target genes that are considered housekeeping genes. These target genes are largely involved in ribosome biogenesis, fatty acid, protein and nucleotide synthesis, nutrient influx or metabolic waste efflux, glycolysis, and glutamine metabolism. MYC's function as a driver of cell growth has been revealed through RNA sequencing, genome-wide chromatin immunoprecipitation, proteomics, and importantly metabolomics, which is highlighted in this chapter.
Topics: Animals; Carcinogenesis; Cell Proliferation; Cell Transformation, Neoplastic; DNA; Genes, myc; Glucose; Glycolysis; Humans; Metabolomics; Neoplasms; Proto-Oncogene Proteins c-myc; RNA Polymerase I; Ribosomes
PubMed: 34019293
DOI: 10.1007/978-1-0716-1476-1_11 -
Aging and Disease Apr 2024Various diseases, including cancers, age-associated disorders, and acute liver failure, have been linked to the oncogene, MYC. Animal testing and clinical trials have... (Review)
Review
Various diseases, including cancers, age-associated disorders, and acute liver failure, have been linked to the oncogene, MYC. Animal testing and clinical trials have shown that sustained tumor volume reduction can be achieved when MYC is inactivated, and different combinations of therapeutic agents including MYC inhibitors are currently being developed. In this review, we first provide a summary of the multiple biological functions of the MYC oncoprotein in cancer treatment, highlighting that the equilibrium points of the MYC/MAX, MIZ1/MYC/MAX, and MAD (MNT)/MAX complexes have further potential in cancer treatment that could be used to restrain MYC oncogene expression and its functions in tumorigenesis. We also discuss the multifunctional capacity of MYC in various cellular cancer processes, including its influences on immune response, metabolism, cell cycle, apoptosis, autophagy, pyroptosis, metastasis, angiogenesis, multidrug resistance, and intestinal flora. Moreover, we summarize the MYC therapy patent landscape and emphasize the potential of MYC as a druggable target, using herbal medicine modulators. Finally, we describe pending challenges and future perspectives in biomedical research, involving the development of therapeutic approaches to modulate MYC or its targeted genes. Patients with cancers driven by MYC signaling may benefit from therapies targeting these pathways, which could delay cancerous growth and recover antitumor immune responses.
Topics: Animals; Humans; Genes, myc; Proto-Oncogene Proteins c-myc; Repressor Proteins; Biological Products; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; Signal Transduction; Neoplasms
PubMed: 37450923
DOI: 10.14336/AD.2023.0520 -
British Journal of Cancer Jan 2016When the genes encoding NF-κB subunits were first isolated, their homology to the previously identified c-Rel proto-oncogene and its viral homologue v-Rel was clear.... (Review)
Review
When the genes encoding NF-κB subunits were first isolated, their homology to the previously identified c-Rel proto-oncogene and its viral homologue v-Rel was clear. This provided the first indication that these transcription factors also had a role in cancer. Because of its homology to v-Rel, which transforms chicken B cells together with the important role c-Rel can have as a regulator of B- and T-cell proliferation, most attention has focussed on its role in B-cell lymphomas, where the REL gene is frequently amplified. However, a growing number of reports now indicate that c-Rel has important functions in many solid tumours, although studies in mice suggest it may not always function as an oncogene. Moreover, c-Rel is a critical regulator of fibrosis, which provides an environment for tumour development in many settings. Overall, c-Rel is emerging as a complex regulator of tumorigenesis, and there is still much to learn about its functions in human malignancies and the response to cancer therapies.
Topics: Animals; Fibrosis; Genes, p53; Genes, rel; Humans; Lymphoma, B-Cell; Mice; Neoplasms; Proto-Oncogene Mas; Proto-Oncogene Proteins c-rel
PubMed: 26757421
DOI: 10.1038/bjc.2015.410 -
Proceedings of the National Academy of... Apr 2023The hypoxia-inducible factor 1-α (HIF-1α) enables cells to adapt and respond to hypoxia (Hx), and the activity of this transcription factor is regulated by several...
The hypoxia-inducible factor 1-α (HIF-1α) enables cells to adapt and respond to hypoxia (Hx), and the activity of this transcription factor is regulated by several oncogenic signals and cellular stressors. While the pathways controlling normoxic degradation of HIF-1α are well understood, the mechanisms supporting the sustained stabilization and activity of HIF-1α under Hx are less clear. We report that ABL kinase activity protects HIF-1α from proteasomal degradation during Hx. Using a fluorescence-activated cell sorting (FACS)-based CRISPR/Cas9 screen, we identified HIF-1α as a substrate of the cleavage and polyadenylation specificity factor-1 (CPSF1), an E3-ligase which targets HIF-1α for degradation in the presence of an ABL kinase inhibitor in Hx. We show that ABL kinases phosphorylate and interact with CUL4A, a cullin ring ligase adaptor, and compete with CPSF1 for CUL4A binding, leading to increased HIF-1α protein levels. Further, we identified the MYC proto-oncogene protein as a second CPSF1 substrate and show that active ABL kinase protects MYC from CPSF1-mediated degradation. These studies uncover a role for CPSF1 in cancer pathobiology as an E3-ligase antagonizing the expression of the oncogenic transcription factors, HIF-1α and MYC.
Topics: Humans; Cullin Proteins; Gene Expression Regulation; Hypoxia; Phosphorylation; Protein Serine-Threonine Kinases; Transcription Factors; Ubiquitin-Protein Ligases; Genes, abl; Hypoxia-Inducible Factor 1, alpha Subunit; Proto-Oncogene Proteins c-myc; Cleavage And Polyadenylation Specificity Factor
PubMed: 37040401
DOI: 10.1073/pnas.2210418120 -
Proceedings of the National Academy of... Aug 2020Quantifying evolutionary dynamics of cancer initiation and progression can provide insights into more effective strategies of early detection and treatment. Here we...
Quantifying evolutionary dynamics of cancer initiation and progression can provide insights into more effective strategies of early detection and treatment. Here we develop a mathematical model of colorectal cancer initiation through inactivation of two tumor suppressor genes and activation of one oncogene, accounting for the well-known path to colorectal cancer through loss of tumor suppressors and and gain of the oncogene. In the model, we allow mutations to occur in any order, leading to a complex network of premalignant mutational genotypes on the way to colorectal cancer. We parameterize the model using experimentally measured parameter values, many of them only recently available, and compare its predictions to epidemiological data on colorectal cancer incidence. We find that the reported lifetime risk of colorectal cancer can be recovered using a mathematical model of colorectal cancer initiation together with experimentally measured mutation rates in colorectal tissues and proliferation rates of premalignant lesions. We demonstrate that the order of driver events in colorectal cancer is determined primarily by the fitness effects that they provide, rather than their mutation rates. Our results imply that there may not be significant immune suppression of untreated benign and malignant colorectal lesions.
Topics: Carcinogenesis; Colonic Neoplasms; Colorectal Neoplasms; Disease Progression; Genes, APC; Genes, p53; Genes, ras; Humans; Models, Theoretical; Mutation; Mutation Rate; Oncogenes; Proto-Oncogene Proteins p21(ras); Tumor Suppressor Protein p53
PubMed: 32788368
DOI: 10.1073/pnas.2003771117 -
Nature Communications Sep 2021Chromosomal rearrangements are a frequent cause of oncogene deregulation in human malignancies. Overexpression of EVI1 is found in a subgroup of acute myeloid leukemia...
Chromosomal rearrangements are a frequent cause of oncogene deregulation in human malignancies. Overexpression of EVI1 is found in a subgroup of acute myeloid leukemia (AML) with 3q26 chromosomal rearrangements, which is often therapy resistant. In AMLs harboring a t(3;8)(q26;q24), we observed the translocation of a MYC super-enhancer (MYC SE) to the EVI1 locus. We generated an in vitro model mimicking a patient-based t(3;8)(q26;q24) using CRISPR-Cas9 technology and demonstrated hyperactivation of EVI1 by the hijacked MYC SE. This MYC SE contains multiple enhancer modules, of which only one recruits transcription factors active in early hematopoiesis. This enhancer module is critical for EVI1 overexpression as well as enhancer-promoter interaction. Multiple CTCF binding regions in the MYC SE facilitate this enhancer-promoter interaction, which also involves a CTCF binding site upstream of the EVI1 promoter. We hypothesize that this CTCF site acts as an enhancer-docking site in t(3;8) AML. Genomic analyses of other 3q26-rearranged AML patient cells point to a common mechanism by which EVI1 uses this docking site to hijack enhancers active in early hematopoiesis.
Topics: Acute Disease; CCCTC-Binding Factor; Chromosomes, Human, Pair 3; Chromosomes, Human, Pair 8; Enhancer Elements, Genetic; Gene Expression Regulation, Leukemic; Gene Rearrangement; High-Throughput Nucleotide Sequencing; Humans; In Situ Hybridization, Fluorescence; K562 Cells; Karyotyping; Leukemia, Myeloid; MDS1 and EVI1 Complex Locus Protein; Promoter Regions, Genetic; Protein Binding; Proto-Oncogene Proteins c-myc; Proto-Oncogenes; Translocation, Genetic
PubMed: 34584081
DOI: 10.1038/s41467-021-25862-3 -
Endocrinology and Metabolism (Seoul,... Mar 2019The development of next generation sequencing (NGS) has led to marked advancement of our understanding of genetic events mediating the initiation and progression of... (Review)
Review
The development of next generation sequencing (NGS) has led to marked advancement of our understanding of genetic events mediating the initiation and progression of thyroid cancers. The NGS studies have confirmed the previously reported high frequency of mutually-exclusive oncogenic alterations affecting and proto-oncogenes in all stages of thyroid cancer. Initially identified by traditional sequencing approaches, the NGS studies also confirmed the acquisition of alterations that inactivate tumor protein p53 () and activate phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha () in advanced thyroid cancers. Novel alterations, such as those in telomerase reverse transcriptase () promoter and mating-type switching/sucrose non-fermenting (SWI/SNF) complex, are also likely to promote progression of the -driven thyroid cancers. A number of genetically engineered mouse models (GEMM) of -driven thyroid cancer have been developed to investigate thyroid tumorigenesis mediated by oncogenic BRAF and to explore the role of genetic alterations identified in the genomic analyses of advanced thyroid cancer to promote tumor progression. This review will discuss the various GEMMs that have been developed to investigate oncogenic -driven thyroid cancers.
Topics: Animals; Carcinoma, Papillary; Class I Phosphatidylinositol 3-Kinases; Disease Progression; High-Throughput Nucleotide Sequencing; Humans; Mice; Mice, Transgenic; Mutation; Promoter Regions, Genetic; Proto-Oncogene Mas; Proto-Oncogene Proteins B-raf; Proto-Oncogenes; Telomerase; Thyroid Neoplasms; Tumor Suppressor Protein p53
PubMed: 30784243
DOI: 10.3803/EnM.2019.34.1.11 -
BMC Medical Genomics Nov 2023Chronic inflammation causes bone destruction in middle ear cholesteatomas (MECs). However, the causes of their neoplastic features remain unknown. The present study...
BACKGROUND
Chronic inflammation causes bone destruction in middle ear cholesteatomas (MECs). However, the causes of their neoplastic features remain unknown. The present study demonstrated for the first time that neoplastic features of MEC are based on proto-oncogene mutations.
RESULTS
DNA was extracted from MEC and blood samples of five patients to detect somatic mutations using depth-depth exome sequencing. Exons with somatic variants were analyzed using an additional 17 MEC/blood test pairs. Variants detected in MECs but not in blood were considered pathogenic variant candidates. We analyzed the correlation between proto-oncogene (NOTCH1 and MYC) variants and the presence of bone destruction and granulation tissue formation. MYC and NOTCH1 variants were detected in two and five of the 22 samples, respectively. Two of the NOTCH1 variants were located in its specific functional domain, one was truncating and the other was a splice donor site variant. Mutations of the two genes in attic cholesteatomas (n = 14) were significantly related with bone destruction (p = 0.0148) but not with granulation tissue formation (p = 0.399).
CONCLUSIONS
This is the first study to demonstrate a relationship between neoplastic features of MEC and proto-oncogene mutations.
Topics: Humans; Cholesteatoma, Middle Ear; Ear, Middle; Mutation; Proto-Oncogenes
PubMed: 37968650
DOI: 10.1186/s12920-023-01640-6 -
Oncotarget Jul 2016The KRAS/ K-RAS oncogene is crucially involved in human cancer. The term "oncogene" -- i.e., a gene able to transform a normal cell into a tumor cell - was introduced in... (Review)
Review
The KRAS/ K-RAS oncogene is crucially involved in human cancer. The term "oncogene" -- i.e., a gene able to transform a normal cell into a tumor cell - was introduced in 1969, but the word was not used in the human carcinogenesis literature until much later. Transforming Kras and Hras oncogenes from the Kirsten and Harvey sarcoma viruses were not identified until the early 1980s due to the complicated structures of the viral genomes. Orthologs of these viral oncogenes were then found in transforming DNA fragments in human cancers in the form of mutated versions of the HRAS and KRAS proto-oncogenes. Thus, RAS genes were the first human oncogenes to be identified. Subsequent studies showed that mutated KRAS acted as an in vivo oncogenic driver, as indicated by studies of anti-EGFR therapy for metastatic colorectal cancers. This review addresses the historical background and experimental studies that led to the discovery of Kirsten Ras as an oncogene, the role of mutated KRAS in human carcinogenesis, and recent therapeutic studies of cancer cells with KRAS mutations.
Topics: Animals; Carcinogenesis; Cloning, Molecular; ErbB Receptors; Genes, ras; Humans; Mice; Mutation; Neoplasms; Proto-Oncogene Proteins p21(ras); Rats
PubMed: 27102293
DOI: 10.18632/oncotarget.8773