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Sato T , Cesaroni M , Chung W , Panjarian S , Tran A , Madzo J , Okamoto Y , Zhang H , Chen X , Jelinek J , Issa JJ
Transcriptional Selectivity of Epigenetic Therapy in Cancer
Cancer Res. 2017 Jan 15;77(2) :470-481
PMID: 27879268    PMCID: PMC5243171    URL: https://www.ncbi.nlm.nih.gov/pubmed/27879268
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A central challenge in the development of epigenetic cancer therapy is the ability to direct selectivity in modulating gene expression for disease-selective efficacy. To address this issue, we characterized by RNA-seq, DNA methylation, and ChIP-seq analyses the epigenetic response of a set of colon, breast, and leukemia cancer cell lines to small-molecule inhibitors against DNA methyltransferases (DAC), histone deacetylases (Depsi), histone demethylases (KDM1A inhibitor S2101), and histone methylases (EHMT2 inhibitor UNC0638 and EZH2 inhibitor GSK343). We also characterized the effects of DAC as combined with the other compounds. Averaged over the cancer cell models used, we found that DAC affected 8.6% of the transcriptome and that 95.4% of the genes affected were upregulated. DAC preferentially regulated genes that were silenced in cancer and that were methylated at their promoters. In contrast, Depsi affected the expression of 30.4% of the transcriptome but showed little selectivity for gene upregulation or silenced genes. S2101, UNC0638, and GSK343 affected only 2% of the transcriptome, with UNC0638 and GSK343 preferentially targeting genes marked with H3K9me2 or H3K27me3, respectively. When combined with histone methylase inhibitors, the extent of gene upregulation by DAC was extended while still maintaining selectivity for DNA-methylated genes and silenced genes. However, the genes upregulated by combination treatment exhibited limited overlap, indicating the possibility of targeting distinct sets of genes based on different epigenetic therapy combinations. Overall, our results demonstrated that DNA methyltransferase inhibitors preferentially target cancer-relevant genes and can be combined with inhibitors targeting histone methylation for synergistic effects while still maintaining selectivity. Cancer Res; 77(2); 470-81. (c)2016 AACR.
Sato, Takahiro Cesaroni, Matteo Chung, Woonbok Panjarian, Shoghag Tran, Anthony Madzo, Jozef Okamoto, Yasuyuki Zhang, Hanghang Chen, Xiaowei Jelinek, Jaroslav Issa, Jean-Pierre J eng P50 CA100632/CA/NCI NIH HHS/ R01 CA158112/CA/NCI NIH HHS/ R01 DE022015/DE/NIDCR NIH HHS/ 2016/11/24 06:00 Cancer Res. 2017 Jan 15;77(2):470-481. doi: 10.1158/0008-5472.CAN-16-0834. Epub 2016 Nov 22.