Mithramycin A suppresses expression of the human melanoma-associated gene ABCB8.
The role of the ABCB8 gene in human cells is poorly understood, although it has been suggested to be involved in multidrug resistance in some types of cancers (e.g., melanomas). In this study, the main mechanism of transcriptional regulation of the ABCB8 gene was characterized. EMSA and ChIP assays revealed that the transcription factor Sp1 binds to the ABCB8 core promoter region, and Sp1 consensus elements were crucial for promoter activity in a luciferase reporter gene assay. Mithramycin A, an inhibitor of Sp1 binding, downregulated the expression of ABCB8 (and other ABC genes) in a concentration-dependent manner and sensitized a melanoma cell line to doxorubicin treatment. These findings may have therapeutic applications in at least a subset of melanoma patients.
Laboratory of Transcriptional Regulation, Institute of Medical Biology, Polish Academy of Sciences, Lodowa 106, 93-232 Lodz, Poland.
Iwona
I
Sachrajda
Marcin
M
Ratajewski
D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors* / Q000235:genetics; D045744:Cell Line, Tumor; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics; D004317:Doxorubicin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics; D024202:Electrophoretic Mobility Shift Assay; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D008545:Melanoma / Q000235:genetics*; D008926:Plicamycin / Q000031:analogs & derivatives* / Q000494:pharmacology; D011401:Promoter Regions, Genetic / Q000187:drug effects; D012878:Skin Neoplasms / Q000235:genetics*; D016329:Sp1 Transcription Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism
D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D016329:Sp1 Transcription Factor; D004317:Doxorubicin; C066851:mithramycin A; D008926:Plicamycin