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

Abstract

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.

Response to Comment on “Epigenetic activation of the drug transporter OCT2 sensitizes renal cell carcinoma to oxaliplatin”

“…At the mRNA level, we found decreased expression of OCT2 mRNA in paired ccRCC tissues, which is supported by both microarray data and reverse transcription quantitative polymerase chain reaction (RT-qPCR) data (1). Because of the variability of OCT2 mRNA expression among persons, the quantification of gene detection based on a paired design (RCC tissues and matched adjacent nontumor collected from the same patients) is crucial to more accurately determine the differential expression.…”

“…Lingmin Yuan, 1 Huidi Jiang, 1 Su Zeng, 1 † ‡ Lushan Yu 1 † ‡ OCT2 plays a key role in synergy between decitabine and oxaliplatin in renal cell carcinoma cell lines.…”

“…We identified the organic cation transporter OCT2 repression as an important factor in oxaliplatin resistance to renal cell carcinoma (RCC) (1). The loss of OCT2 expression at both transcription and protein levels was determined in collected paired patient tissues, commercial tissue microarray specimens, and RCC cell lines.…”

The tales of two organic cation transporters, OCT-1 and OCT-2, in C. elegans

“…For example, the SLC35F2 transporter is completely responsible for the uptake into human tumour cells of the anticancer drug YM155, which is currently in clinical evaluation [12]. Another recent study established that the organic cation transporter SLC22A2 (OCT2) is required for oxaliplatin uptake into renal cells and that downregulation of OCT2 is a cause for oxaliplatin resistance in renal cell carcinoma [13]. However, these resistant renal cell carcinoma can be sensitized to oxaliplatin upon restoring OCT2 expression [13].…”

“…Another recent study established that the organic cation transporter SLC22A2 (OCT2) is required for oxaliplatin uptake into renal cells and that downregulation of OCT2 is a cause for oxaliplatin resistance in renal cell carcinoma [13]. However, these resistant renal cell carcinoma can be sensitized to oxaliplatin upon restoring OCT2 expression [13]. In a final example, the functional level of another member of the organic cation transporter family, SLC22A1 (OCT1), was shown to be a critical marker for the responses of chronic-phase chronic myeloid leukemia towards the tyrosine kinase inhibitor imatinib [14].…”