Different Involvement of Promoter Methylation in the Expression of Organic Cation-Carnitine Transporter 2 OCTN2 in Cancer Cell LinesReport as inadecuate




Different Involvement of Promoter Methylation in the Expression of Organic Cation-Carnitine Transporter 2 OCTN2 in Cancer Cell Lines - Download this document for free, or read online. Document in PDF available to download.

Organic cation-carnitine transporter 2 OCTN2 is responsible for the cellular uptake of the antineoplastic agent, oxaliplatin. Epigenetic modification is a possible mechanism of altered drug-transporter expression in cancers, leading to altered efficacy of chemotherapeutic drugs. However, the mechanisms governing OCTN2 regulation are not completely understood. In this study, the low levels of OCTN2 in HepG2 and LS174T cells were elevated by the demethylating reagent, decitabine DCA. To further reveal the epigenetic mechanism of down-regulation of OCTN2, we found that Region-1 within the OCTN2 promoter spanning −354 to +85 was a determinant of OCTN2 expression in a luciferase reporter assay. Moreover, methylation-specific PCR MSP and bisulfite genomic sequencing showed that the degree of individual methylated CpG sites within this region was inversely correlated with the levels of OCTN2 in different cancer cells. Application of DCA to HepG2 and LS174T cells reversed the hypermethylation status of the OCTN2 promoter and increased OCTN2 expression, enhancing cellular uptake of oxaliplatin. Thus, we identified that promoter methylation is responsible for epigenetic down-regulation of OCTN2 in HepG2 and LS174T cells. Given the essential role of OCTN2 in cancer cell uptake of chemotherapeutics, and thus treatment efficacy, pretreatment with a demethylating reagent is a possible strategy for optimizing pharmacotherapies against cancers.



Author: Qiang Qu, Jian Qu, Min Zhan, Lan-Xiang Wu, Yi-Wen Zhang, Xiao-Ya Lou, Li-Juan Fu, Hong-Hao Zhou

Source: http://plos.srce.hr/



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