Promoter methylation patterns of ABCB1, ABCC1 and ABCG2 in human cancer cell lines, multidrug-resistant cell models and tumor, tumor-adjacent and tumor-distant tissues from breast cancer patients

Abstract

Overexpression of ABCB1, ABCC1 and ABCG2 in tumor tissues is considered a major cause of limited efficacy of anticancer drugs. Gene expression of ABC transporters is regulated by multiple mechanisms, including changes in the DNA methylation status. Most of the studies published so far only report promoter methylation levels for either ABCB1 or ABCG2, and data on the methylation status for ABCC1 are scarce. Thus, we determined the promoter methylation patterns of ABCB1, ABCC1 and ABCG2 in 19 human cancer cell lines. In order to contribute to the elucidation of the role of DNA methylation changes in acquisition of a multidrug resistant (MDR) phenotype, we also analyzed the promoter methylation patterns in drug-resistant sublines of the cancer cell lines GLC-4, SW1573, KB-3-1 and HL-60. In addition, we investigated if aberrant promoter methylation levels of ABCB1, ABCC1 and ABCG2 occur in tumor and tumor-surrounding tissues from breast cancer patients.Our data indicates that hypomethylation of the ABCC1 promoter is not cancer type-specific but occurs in cancer cell lines of different origins. Promoter methylation was found to be an important mechanism in gene regulation of ABCB1 in parental cancer cell lines and their drug-resistant sublines. Overexpression of ABCC1 in MDR cell models turned out to be mediated by gene amplification, not by changes in the promoter methylation status of ABCC1. In contrast to the promoters of ABCC1 and ABCG2, the promoter of ABCB1 was significantly higher methylated in tumor tissues than in tumor-adjacent and tumor-distant tissues from breast cancer patients.

MicroRNA-212/ABCG2-axis contributes to development of imatinib-resistance in leukemic cells

“…To analyze ABCG2 methylation, we examined 4 CpGs in a region of 360 bp in the ABCG2 promoter region. We did not observe any changes in methylation of these 4 CpGs during the development of IM-resistance, these findings are in line with those of different cancer entities, such as glioblastoma multiforme [ 50 ], breast-cancer [ 26 ] or multiple myeloma [ 51 ], where no or only partial impact of ABCG2 methylation could be observed. For ABCB1 , we did not observe changes in methylation during the development of IM-resistance.…”

“…In several cancer entities, aberrant ABCB1 or ABCG2 methylation was shown, i.e. in leukemia or solid tumors [ 23 – 25 ] and was also observed in drug-resistance [ 26 , 27 ]. In CML patients, aberrant DNA methylation of various genes could be associated to disease progression and potentially, IM-resistance [ 28 ].…”

HOXA5 is a tumor suppressor gene that is decreased in gastric cancer

“…Our data suggested that HOXA5 inhibited the progression of GC. In order to further explore the underlying mechanisms, we used RT-qPCR to detect the expression of the following genes in 30 GC tissues, including tumorigenesis-related genes ( p21, p53 and β-catenin ), proliferation-related genes ( cyclin B1, cyclin D1, c-Myc and Ki67 ), angiogenesis-related genes [vascular endothelial growth factor ( VEGF ) A, VEGFR2 and epidermal growth factor ( EGFR )], metastasis-related genes [matrix metalloproteinase ( MMP2 ) and ( MMP7 )], apoptosis-related genes ( BCL2 and caspase-3 ), EMT markers (vimentin, N-cadherin and E-cadherin), stemness markers ( Lgr5, CD44 and EpCAM ) and multi-drug resistance genes ( ABCC1, ABCG2 and Beclin1) ( 10 – 15 ). A Spearman's correlation model was used to examine the correlation between each of these genes and HOXA5 mRNA expression.…”

Down-regulation of miR-210-3p encourages chemotherapy resistance of renal cell carcinoma via modulating ABCC1

“…ATP-binding cassette transporter super-family has vital effect on MDR in cancer, which is reported to a main leading cause of chemotherapeutic failure in various cancers through regulating the efflux of chemotherapeutic drugs [ 15 – 18 ]. Previous reports have exhibited ABCC1 to be up-regulated in colorectal cancer [ 19 ], lung cancer [ 20 ], and breast cancer [ 21 ]. MDR-1 serving as a protein scavenger also can capture and transport various chemotherapeutic agents out of cells [ 22 ].…”