Enhanced MYC association with the NuA4 histone acetyltransferase complex mediated by the adenovirus E1A N-terminal domain activates a subset of MYC target genes highly expressed in cancer cells.

Ling-Jun Zhao,Paul M Loewenstein,Maurice Green

doi:10.18632/genesandcancer.160

Abstract

The proto-oncogene MYC is a transcription factor over-expressed in many cancers and required for cell survival. Its function is regulated by histone acetyltransferase (HAT) complexes, such as the GCN5 complex and the NuA4/Tip60 complex. However, the roles of the HAT complexes during MYC function in cancer have not been well characterized. We recently showed that adenovirus E1A and its N-terminal 80 aa region, E1A 1-80, interact with the NuA4 complex, through the E1A TRRAP-targeting (ET) domain, and enhance MYC association with the NuA4 complex. We show here that the ET domain mainly targets the MYC-NuA4 complex. By global gene expression analysis using E1A 1-80 and deletion mutants, we have identified a panel of genes activated by targeting the MYC-NuA4 complex and notably enriched for genes involved in ribosome biogenesis and gene expression. A second panel of genes is activated by E1A 1-80 targeting of both the MYC-NuA4 complex and p300, and is enriched for genes involved in DNA replication and cell cycle processes. Both panels of genes are highly expressed in cancer cells. Since the ET domain is essential for E1A-mediated cellular transformation, our results suggest that MYC and the NuA4 complex function cooperatively in cell transformation and cancer.

Highlights

The proto-oncogene MYC is a transcription factor over-expressed in many cancers and required for cell survival
Significant over-expression of a similar set of genes in human cancers seems to be correlated with tumor invasiveness, suggesting the importance of MYC association with the
1-80 and mutants lacking a functional E1A TRRAP-targeting (ET) domain or p300targeting domain, and identified two panels of genes that are activated by E1A 1-80 targeting of the MYC-NuA4 complex or by targeting of both the MYC-NuA4 complex and p300

Summary

Introduction

The proto-oncogene MYC is a transcription factor over-expressed in many cancers and required for cell survival. NuA4 complex (see Figure 1A) in the absence of potential interference from p300-targeting, and may help reveal genes activated by the enhanced MYC association with the NuA4 complex. B. Activation of selected MNA4 panel genes involved in ribosome biogenesis/gene expression by RT-qPCR analysis.

Results

Conclusion