Abstract
The MYC oncogene has been implicated in the regulation of up to thousands of genes involved in many cellular programs including proliferation, growth, differentiation, self-renewal, and apoptosis. MYC is thought to induce cancer through an exaggerated effect on these physiologic programs. Which of these genes are responsible for the ability of MYC to initiate and/or maintain tumorigenesis is not clear. Previously, we have shown that upon brief MYC inactivation, some tumors undergo sustained regression. Here we demonstrate that upon MYC inactivation there are global permanent changes in gene expression detected by microarray analysis. By applying StepMiner analysis, we identified genes whose expression most strongly correlated with the ability of MYC to induce a neoplastic state. Notably, genes were identified that exhibited permanent changes in mRNA expression upon MYC inactivation. Importantly, permanent changes in gene expression could be shown by chromatin immunoprecipitation (ChIP) to be associated with permanent changes in the ability of MYC to bind to the promoter regions. Our list of candidate genes associated with tumor maintenance was further refined by comparing our analysis with other published results to generate a gene signature associated with MYC-induced tumorigenesis in mice. To validate the role of gene signatures associated with MYC in human tumorigenesis, we examined the expression of human homologs in 273 published human lymphoma microarray datasets in Affymetrix U133A format. One large functional group of these genes included the ribosomal structural proteins. In addition, we identified a group of genes involved in a diverse array of cellular functions including: BZW2, H2AFY, SFRS3, NAP1L1, NOLA2, UBE2D2, CCNG1, LIFR, FABP3, and EDG1. Hence, through our analysis of gene expression in murine tumor models and human lymphomas, we have identified a novel gene signature correlated with the ability of MYC to maintain tumorigenesis.
Highlights
Overexpression of MYC is one of the most frequent events in human tumorigenesis [1]
We have shown that even the brief inactivation of the MYC oncogene can result in the sustained regression of at least some tumors
We have utilized several novel genomic analyses to define a set of genes that strongly correlate with the ability of the MYC oncogene to maintain tumorigenesis
Summary
Overexpression of MYC is one of the most frequent events in human tumorigenesis [1]. MYC overexpression is thought to induce tumorigenesis by causing inappropriate gene expression resulting in autonomous cellular growth, proliferation, and the inhibition of cellular differentiation [2,3]. Many laboratories have conditionally overexpressed c-MYC (MYC) utilizing conditional transgenic model systems [4,5,6,7,8,9] In these models, the suppression of MYC led to permanent loss of tumorigenesis through proliferative arrest, differentiation and/or apoptosis [4,5,6,10]. Even the brief suppression of MYC overexpression permanently prevents its ability to sustain tumorigenesis [6]. These and other observations have suggested the possibility that oncogenes such as MYC exhibit the phenomena of oncogene addiction [11]. We have suggested that cellular senescence, which involves chromatin modifications and heterochromatin formation [12,13], may be an important mechanism for sustained tumor regression upon MYC inactivation [14]
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