Epigenetic reprogramming of the mesenchymal state by SUV39H1/H2 [RNA-Seq]

Emergence of chemotherapy resistance is a major clinical challenge resulting in large number of deaths yearly. One mechanism involves epigenetic reprogramming through which cancer cells acquire mesenchymal (M) properties akin to cancer stem cells. How cells epigenetically establish resistance to chemotherapy is largely unknown. Here, we show that the two human lysine 9 histone H3 (H3K9) methyltransferase proteins (SUV39H1 and SUV39H2) play a central role in maintaining mesenchymal, chemotherapy resistant state in several cancer models. More importantly, a transient inhibition of these enzymes results in an epigenetic change, triggering a mesenchymal-to-epithelial transition and sensitizing these cells to chemotherapy. These data expand the functional repertoire of SUV39H family of proteins in eukaryotes and expose new therapeutic targets for neutralizing chemotherapy resistance in cancers. Overall design: Transcriptome of HMLE and HMLE-TWIST1 cells treated with DMSO, different doses of chaetocin, or in which SUV39H1/H2 were knocked down for two or four days were generated using next-generation high-throughput sequencing in triplicates.