Direct and coordinate regulation of ATP-binding cassette transporter genes by Myc factors generates specific transcription signatures that significantly affect the chemoresistance phenotype of cancer cells.
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.
Department of Biology, University of Bologna, Bologna 40126, Italy.
Antonio
A
Porro
Michelle
M
Haber
Daniel
D
Diolaiti
Nunzio
N
Iraci
Michelle
M
Henderson
Samuele
S
Gherardi
Emanuele
E
Valli
Marcia A
MA
Munoz
Chengyuan
C
Xue
Claudia
C
Flemming
Manfred
M
Schwab
Jason H
JH
Wong
Glenn M
GM
Marshall
Giuliano
G
Della Valle
Murray D
MD
Norris
Giovanni
G
Perini
D018528:ATP-Binding Cassette Transporters / Q000378:metabolism*; D001932:Brain Neoplasms / Q000378:metabolism; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D020869:Gene Expression Profiling; D006801:Humans; D020128:Inhibitory Concentration 50; D008957:Models, Genetic; D009369:Neoplasms / Q000378:metabolism*; D010641:Phenotype; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*; D012175:Retinoblastoma / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism*; D014158:Transcription, Genetic
D018528:ATP-Binding Cassette Transporters; D016271:Proto-Oncogene Proteins c-myc; D014157:Transcription Factors