Elevated level of lysine 9-acetylated histone H3 at the MDR1 promoter in multidrug-resistant cells.
Failure of chemotherapy in breast cancer presents a major problem and is often due to elevated expression of ATP binding cassette (ABC)-type transporters, such as MDR1 protein. It has been shown that MDR1/ABCB1 gene expression is regulated at the chromatin level by DNA methylation and histone acetylation. However, the modified histone residues have not been identified and the role of various histone acetyl transferases (HATs) is not fully understood. By studying a breast carcinoma model cell line and its MDR1-overexpressing derivative, we show that the histone 3 lysine 9 (H3K9) acetylation level is elevated 100-fold in the promoter and first exon of the MDR1 gene in the drug-resistant cell line compared to the drug-sensitive cell line. The acetylation level of the other examined lysine residues (H3K4, H3K14, H4K8, and H4K12) is weakly or not at all elevated in the MDR1 locus, although their acetylation is generally increased genome-wide in the drug-resistant cell. Downregulation of the expression of HATs PCAF and GCN5 by RNAi effectively reduces the expression of MDR1. Unexpectedly, treatment with a p300-selective inhibitor (HAT inhibitor II) further increases MDR1 expression and drug efflux in the drug-resistant cells. Our data suggest that repeated exposure to chemotherapy may result in deregulated histone acetylation genome-wide and in the MDR1 promoter.
Institute for Plant Genomics, Human Biotechnology and Bioenergy (BAYGEN), Bay Zoltan Foundation for Applied Research, Szeged, Hungary.
Monika
M
Toth
Imre M
IM
Boros
Eva
E
Balint
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics*; D000107:Acetylation; D001943:Breast Neoplasms / Q000235:genetics*; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000494:pharmacology; D018432:Drug Resistance, Multiple / Q000235:genetics*; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D051548:Histone Acetyltransferases / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006657:Histones / Q000378:metabolism*; D006801:Humans; D008239:Lysine / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D034622:RNA Interference; D050880:p300-CBP Transcription Factors / Q000235:genetics; D000099224:p300-CBP-Associated Factor
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D004317:Doxorubicin; D051548:Histone Acetyltransferases; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D008239:Lysine; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor; C513055:ABCB1 protein, human