The MYC oncogene — the grand orchestrator of cancer growth and immune evasion

Dhanasekaran, Renumathy; Deutzmann, Anja; Mahauad‐Fernandez, Wadie D.; Hansen, Aida S.; Gouw, Arvin M.; Felsher, Dean W.

doi:10.1038/s41571-021-00549-2

Cited by 443 publications

(300 citation statements)

References 223 publications

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“…Together with c-Myc and L-Myc, N-Myc constitutes a very potent network of transcription factors, regulating the expression of a massive group of genes implicated in cell cycle progression, protein translation, and metabolism [ 8 , 9 ]. Such transcription factors are usually found upregulated in various cancers in humans [ 10 ]. The structural organization of Myc proteins shares conserved motifs called “Myc Boxes” (MB), which serve as a docking site for protein–protein interactions.…”

Section: Introductionmentioning

confidence: 99%

PHA-680626 Is an Effective Inhibitor of the Interaction between Aurora-A and N-Myc

Boi

Souvalidou

Capelli

et al. 2021

IJMS

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Neuroblastoma is a severe childhood disease, accounting for ~10% of all infant cancers. The amplification of the MYCN gene, coding for the N-Myc transcription factor, is an essential marker correlated with tumor progression and poor prognosis. In neuroblastoma cells, the mitotic kinase Aurora-A (AURKA), also frequently overexpressed in cancer, prevents N-Myc degradation by directly binding to a highly conserved N-Myc region. As a result, elevated levels of N-Myc are observed. During recent years, it has been demonstrated that some ATP competitive inhibitors of AURKA also cause essential conformational changes in the structure of the activation loop of the kinase that prevents N-Myc binding, thus impairing the formation of the AURKA/N-Myc complex. In this study, starting from a screening of crystal structures of AURKA in complexes with known inhibitors, we identified additional compounds affecting the conformation of the kinase activation loop. We assessed the ability of such compounds to disrupt the interaction between AURKA and N-Myc in vitro, using Surface Plasmon Resonance competition assays, and in tumor cell lines overexpressing MYCN, by performing Proximity Ligation Assays. Finally, their effects on N-Myc cellular levels and cell viability were investigated. Our results identify PHA-680626 as an amphosteric inhibitor both in vitro and in MYCN overexpressing cell lines, thus expanding the repertoire of known conformational disrupting inhibitors of the AURKA/N-Myc complex and confirming that altering the conformation of the activation loop of AURKA with a small molecule is an effective strategy to destabilize the AURKA/N-Myc interaction in neuroblastoma cancer cells.

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Section: Introductionmentioning

confidence: 99%

PHA-680626 Is an Effective Inhibitor of the Interaction between Aurora-A and N-Myc

Boi

Souvalidou

Capelli

et al. 2021

IJMS

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“…MYC and MYEOV are two well-known oncogenes ( Specht et al, 2004 ; Paglia et al, 2020 ). MYC can contribute to oncogenesis and immune evasion through various mechanisms, including the promotion of autonomous cell growth and proliferation, modulation of tumor–stroma interactions, and regulation of the host immune system ( Dang, 2012 ; Paglia et al, 2020 ; Dhanasekaran et al, 2021 ; Lourenco et al, 2021 ), while the mechanism of action that underlies the function of MYEOV in cancer development and metastasis may enhance SOX9 transcriptional activity ( Lawlor et al, 2010 ; Fang et al, 2019 ; Liang et al, 2020 ). Thus, both MYC and MYEOV have also been identified as potential immunotherapy targets ( Fang et al, 2019 ; Duffy et al, 2021 ).…”

Section: Discussionmentioning

confidence: 99%

Construction and Clinical Translation of Causal Pan-Cancer Gene Score Across Cancer Types

Tao

Pan

et al. 2021

Front. Genet.

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Pan-cancer strategy, an integrative analysis of different cancer types, can be used to explain oncogenesis and identify biomarkers using a larger statistical power and robustness. Fine-mapping defines the casual loci, whereas genome-wide association studies (GWASs) typically identify thousands of cancer-related loci and not necessarily have a fine-mapping component. In this study, we develop a novel strategy to identify the causal loci using a pan-cancer and fine-mapping assumption, constructing the CAusal Pan-cancER gene (CAPER) score and validating its performance using internal and external validation on 1,287 individuals and 985 cell lines. Summary statistics of 15 cancer types were used to define 54 causal loci in 15 potential genes. Using the Cancer Genome Atlas (TCGA) training set, we constructed the CAPER score and divided cancer patients into two groups. Using the three validation sets, we found that 19 cancer-related variables were statistically significant between the two CAPER score groups and that 81 drugs had significantly different drug sensitivity between the two CAPER score groups. We hope that our strategies for selecting causal genes and for constructing CAPER score would provide valuable clues for guiding the management of different types of cancers.

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“…SKP2 also targets P27 ( CDKN1B ) for proteolytic degradation, a cell cycle regulating protein that inhibits Cyclin Dependent Kinase activity [ 56 ]. Importantly, aberrant P27 accumulation is associated with chromosome instability (CIN; ongoing changes in chromosome numbers) and mitotic defects [ 2 , 53 , 57 ], whereas aberrant Cyclin E1 and c-MYC turnover lead to cell cycle and apoptotic defects that promote cancer development and progression [ 9 , 10 , 12 , 58 , 59 , 60 , 61 ]. In fact, increased c-Myc expression in mouse embryonic fibroblasts increases growth rate, enhances clonogenic growth, decreases in contact inhibition and spontaneously forms tumors in mice within 10 days [ 62 ], providing strong evidence that deregulated c-MYC expression exhibits a significant role in tumorigenesis.…”

Section: Discussionmentioning

confidence: 99%

A Comprehensive Assessment of Genetic and Epigenetic Alterations Identifies Frequent Variations Impacting Six Prototypic SCF Complex Members

Gudiño

Farrell

Neudorf

et al. 2021

IJMS

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The SKP1, CUL1, F-box protein (SCF) complex represents a family of 69 E3 ubiquitin ligases that poly-ubiquitinate protein substrates marking them for proteolytic degradation via the 26S proteasome. Established SCF complex targets include transcription factors, oncoproteins and tumor suppressors that modulate cell cycle activity and mitotic fidelity. Accordingly, genetic and epigenetic alterations involving SCF complex member genes are expected to adversely impact target regulation and contribute to disease etiology. To gain novel insight into cancer pathogenesis, we determined the prevalence of genetic and epigenetic alterations in six prototypic SCF complex member genes (SKP1, CUL1, RBX1, SKP2, FBXW7 and FBXO5) from patient datasets extracted from The Cancer Genome Atlas (TCGA). Collectively, ~45% of observed SCF complex member mutations are predicted to impact complex structure and/or function in 10 solid tumor types. In addition, the distribution of encoded alterations suggest SCF complex members may exhibit either tumor suppressor or oncogenic mutational profiles in a cancer type dependent manner. Further bioinformatic analyses reveal the potential functional implications of encoded alterations arising from missense mutations by examining predicted deleterious mutations with available crystal structures. The SCF complex also exhibits frequent copy number alterations in a variety of cancer types that generally correspond with mRNA expression levels. Finally, we note that SCF complex member genes are differentially methylated across cancer types, which may effectively phenocopy gene copy number alterations. Collectively, these data show that SCF complex member genes are frequently altered at the genetic and epigenetic levels in many cancer types, which will adversely impact the normal targeting and timely destruction of protein substrates, which may contribute to the development and progression of an extensive array of cancer types.

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The MYC oncogene — the grand orchestrator of cancer growth and immune evasion

Cited by 443 publications

References 223 publications

PHA-680626 Is an Effective Inhibitor of the Interaction between Aurora-A and N-Myc

PHA-680626 Is an Effective Inhibitor of the Interaction between Aurora-A and N-Myc

Construction and Clinical Translation of Causal Pan-Cancer Gene Score Across Cancer Types

A Comprehensive Assessment of Genetic and Epigenetic Alterations Identifies Frequent Variations Impacting Six Prototypic SCF Complex Members

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