Epigenetic activation of the drug transporter OCT2 sensitizes renal cell carcinoma to oxaliplatin

Autor: Qinqin Yu, Lushan Yu, Yanqing Liu, Huidi Jiang, Fuqing Tan, Hua Wang, Qianying Zhu, Lingmin Yuan, Xiaoli Zheng, Su Zeng
Rok vydání: 2016
Předmět:
Zdroj: Science Translational Medicine. 8
ISSN: 1946-6242
1946-6234
DOI: 10.1126/scitranslmed.aaf3124
Popis: Renal cell carcinoma (RCC) is known for its multidrug resistance. Using data obtained from the cancer transcriptome database Oncomine and the proteome database The Human Protein Atlas, we identified the repression of organic cation transporter OCT2 as a potential factor contributing to oxaliplatin resistance in RCC. By analyzing OCT2 expression in collected patient tissues and commercial tissue microarray specimens, we demonstrated OCT2 repression in RCC at both transcription and protein levels. Epigenetic analysis revealed that the repressed OCT2 promoter in RCC is characterized by hypermethylated CpG islands and the absence of H3K4 methylation. Further mechanistic studies showed that DNA hypermethylation blocked MYC activation of OCT2 by disrupting its interaction with the E-Box motif, which prevented MYC from recruiting MLL1 to catalyze H3K4me3 at the OCT2 promoter and resulted in repressed OCT2 transcription. Targeting this mechanism, we designed a sequential combination therapy and demonstrated that epigenetic activation of OCT2 by decitabine sensitizes RCC cells to oxaliplatin both in vitro and in xenografts. Our study highlights the potential of translating “omics” data into the development of targeted therapies.
Databáze: OpenAIRE
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