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Transcriptional Activation of MYC-Induced Genes by GCN5 Promotes B-cell Lymphomagenesis.

ABSTRACT: Overexpression of the MYC oncoprotein is an initiating step in the formation of several cancers. MYC frequently recruits chromatin-modifying complexes to DNA to amplify the expression of cancer-promoting genes, including those regulating cell cycle, proliferation, and metabolism, yet the roles of specific modifiers in different cancer types are not well defined. Here, we show that GCN5 is an essential coactivator of cell-cycle gene expression driven by MYC overexpression and that deletion of Gcn5 delays or abrogates tumorigenesis in the Eμ-Myc mouse model of B-cell lymphoma. Our results demonstrate that Gcn5 loss impacts both expression and downstream functions of Myc. SIGNIFICANCE: Our results provide important proof of principle for Gcn5 functions in formation and progression of Myc-driven cancers, suggesting that GCN5 may be a viable target for development of new cancer therapies.

SUBMITTER: Farria AT

PROVIDER: S-EPMC7744430 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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Transcriptional Activation of MYC-Induced Genes by GCN5 Promotes B-cell Lymphomagenesis.

Farria Aimee T AT Plummer Joshua B JB Salinger Andrew P AP Shen Jianjun J Lin Kevin K Lu Yue Y McBride Kevin M KM Koutelou Evangelia E Dent Sharon Y R SYR

Cancer research 20201109 24

Overexpression of the MYC oncoprotein is an initiating step in the formation of several cancers. MYC frequently recruits chromatin-modifying complexes to DNA to amplify the expression of cancer-promoting genes, including those regulating cell cycle, proliferation, and metabolism, yet the roles of specific modifiers in different cancer types are not well defined. Here, we show that GCN5 is an essential coactivator of cell-cycle gene expression driven by MYC overexpression and that deletion of <i> ...[more]

PMID: 33168647

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Gcn5 transcriptional activation of Myc-induced genes promotes B-cell lymphomagenesis

Project description:Purpose: In this study we sought to elucidate whether Gcn5 cooperates with Myc to induce the formation of lymphoma using an in vivo model, the Eµ-Myc mouse. In order to define the molecular mechanisms for how Gcn5 contributes to lymphoma development upon overexpression of Myc, we performed RNA-seq analyses on total RNA isolated from CD19+ B cells sorted from spleens of 5-6-week-old wild-type, Eµ-Myc, and Eµ-Myc; Gcn5Fx/Fx mice. Conclusions: Loss of Gcn5 not only ameliorates dysregulation of the cell cycle caused by Myc overexpression, but also affects Myc-induced pathways related to cancer cell growth.

2020-12-29 | GSE154108 | GEO

Gcn5 transcriptional activation of Myc-induced genes promotes B-cell lymphomagenesis

Project description:Gcn5 transcriptional activation of Myc-induced genes promotes B-cell lymphomagenesis

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Activation-induced cytidine deaminase (AID) promotes B cell lymphomagenesis in Emu-cmyc transgenic mice.

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Specific tumor suppressor function for E2F2 in Myc-induced T cell lymphomagenesis.

Project description:Deregulation of the Myc pathway and deregulation of the Rb pathway are two of the most common abnormalities in human malignancies. Recent in vitro experiments suggest a complex cross-regulatory relationship between Myc and Rb that is mediated through the control of E2F. To evaluate the functional connection between Myc and E2Fs in vivo, we used a bitransgenic mouse model of Myc-induced T cell lymphomagenesis and analyzed tumor progression in mice deficient for E2f1, E2f2, or E2f3. Whereas the targeted inactivation of E2f1 or E2f3 had no significant effect on tumor progression, loss of E2f2 accelerated lymphomagenesis. Interestingly, loss of a single copy of E2f2 also accelerated tumorigenesis, albeit to a lesser extent, suggesting a haploinsufficient function for this locus. The combined ablation of E2f1 or E2f3, along with E2f2, did not further accelerate tumorigenesis. Myc-overexpressing T cells were more resistant to apoptosis in the absence of E2f2, and the reintroduction of E2F2 into these tumor cells resulted in an increase of apoptosis and inhibition of tumorigenesis. These results identify the E2f2 locus as a tumor suppressor through its ability to modulate apoptosis.

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Role of MYC in B Cell Lymphomagenesis.

Project description:B cell lymphomas mainly arise from different developmental stages of B cells in germinal centers of secondary lymphoid tissue. There are a number of signaling pathways that affect the initiation and development of B cell lymphomagenesis. The functions of several key proteins that represent branching points of signaling networks are changed because of their aberrant expression, degradation, and/or accumulation, and those events determine the fate of the affected B cells. One of the most influential transcription factors, commonly associated with unfavorable prognosis for patients with B cell lymphoma, is nuclear phosphoprotein MYC. During B cell lymphomagenesis, oncogenic MYC variant is deregulated through various mechanisms, such as gene translocation, gene amplification, and epigenetic deregulation of its expression. Owing to alterations of downstream signaling cascades, MYC-overexpressing neoplastic B cells proliferate rapidly, avoid apoptosis, and become unresponsive to most conventional treatments. This review will summarize the roles of MYC in B cell development and oncogenesis, as well as its significance for current B cell lymphoma classification. We compared communication networks within transformed B cells in different lymphomas affected by overexpressed MYC and conducted a meta-analysis concerning the association of MYC with tumor prognosis in different patient populations.

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