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Abstract
Increased expression of specific ATP-binding cassette (ABC) transporters is known to mediate the efflux of chemotherapeutic agents from cancer cells. Therefore, establishing how ABC transporter genes are controlled at their transcription level may help provide insight into the role of these multifaceted transporters in the malignant phenotype. We have investigated ABC transporter gene expression in a large neuroblastoma data set of 251 tumor samples. Clustering analysis demonstrated a strong association between differential ABC gene expression patterns in tumor samples and amplification of the MYCN oncogene, suggesting a correlation with MYCN function. Using expression profiling and chromatin immunoprecipitation studies, we show that MYCN oncoprotein coordinately regulates transcription of specific ABC transporter genes, by acting as either an activator or a repressor. Finally, we extend these notions to c-MYC showing that it can also regulate the same set of ABC transporter genes in other tumor cells through similar dynamics. Overall our findings provide insight into MYC-driven molecular mechanisms that contribute to coordinate transcriptional regulation of a large set of ABC transporter genes, thus affecting global drug efflux.
Highlights
Chemoresistance can be due to several cellular mechanisms, including those related to the altered activity of specific ATP
A Specific Transcription Signature of ATP-binding cassette (ABC) Transporter Genes Correlates with MYCN Amplification and Reduced Survival in Neuroblastoma—To understand whether the transcription profiles of multiple human ABC genes are relevant for predict
In this study we have shown that MYCN can coordinate transcription of a large set of ABC transporter genes, whose level of expression is strongly associated with clinical outcome in an aggressive childhood malignancy
Summary
Chemoresistance can be due to several cellular mechanisms, including those related to the altered activity of specific ATP-. The dissection of the molecular mechanisms underlying transcription regulation of ABC genes should enhance the understanding and prediction of drug response as recently proposed by Gottesman and co-workers [15]. Most such mechanistic studies have focused on the ABCB1/MDR1 gene [16], and very few data have been collected on the transcriptional regulation of other ABC genes in normal and tumor tissues. In this study we identified a specific transcription signature of ABC transporter genes dictated by MYC oncoproteins that may provide additional value to the understanding of how a chemoresistance phenotype is established during cancer progression
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