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Opening a door into cancer cells
Renal cell carcinoma is a common cancer that is often resistant to chemotherapy. To address this, Liu et al. investigated the role of OCT2, a protein that normally transports oxaliplatin, a common chemotherapy drug, into cells. The authors found that OCT2 was epigenetically silenced in renal cancer and figured out the underlying mechanism, then designed a combination therapy with decitabine, a drug that reverses epigenetic silencing of OCT2, followed by oxaliplatin, and demonstrated its effectiveness in mouse models. The researchers also found that MATE-2K, another transporter that normally pumps oxaliplatin out of renal cells into the urine, is repressed in cancer cells regardless of decitabine treatment, so oxaliplatin accumulates in treated cancer cells, but not in the surrounding normal tissues.
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.
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