// Abdullah Al Emran 1,* , Diego M. Marzese 2,* , Dinoop Ravindran Menon 1 , Mitchell S. Stark 1 , Joachim Torrano 1 , Heinz Hammerlindl 1 , Gao Zhang 4 , Patricia Brafford 4 , Matthew P. Salomon 2 , Nellie Nelson 3 , Sabrina Hammerlindl 1 , Deepesh Gupta 1 , Gordon B. Mills 5 , Yiling Lu 5 , Richard A. Sturm 1 , Keith Flaherty 6 , Dave S. B. Hoon 2 , Brian Gabrielli 7 , Meenhard Herlyn 4 and Helmut Schaider 1 1 Dermatology Research Centre, The University of Queensland Diamantina Institute, The University of Queensland, Translational Research Institute, Brisbane, Australia 2 Department of Translational Molecular Medicine, John Wayne Cancer Institute, Santa Monica, CA, USA 3 Sequencing Center, John Wayne Cancer Institute, Santa Monica, CA, USA 4 The Wistar Institute, Philadelphia, PA, USA 5 MD Anderson Centre, Houston, TX, USA 6 Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA 7 Mater Research Institute, Translational Research Institute, The University of Queensland, Woolloongabba, Queensland, Australia * These authors have contributed equally to this study Correspondence to: Helmut Schaider, email: // Keywords : acquired drug resistance; stress-induced resistance; histone modification; DNA methylation; epigenetic reprogramming Received : October 07, 2017 Accepted : November 26, 2017 Published : December 24, 2017 Abstract Besides somatic mutations or drug efflux, epigenetic reprogramming can lead to acquired drug resistance. We recently have identified early stress-induced multi-drug tolerant cancer cells termed induced drug-tolerant cells (IDTCs). Here, IDTCs were generated using different types of cancer cell lines; melanoma, lung, breast and colon cancer. A common loss of the H3K4me3 and H3K27me3 and gain of H3K9me3 mark was observed as a significant response to drug exposure or nutrient starvation in IDTCs. These epigenetic changes were reversible upon drug holidays. Microarray, qRT-PCR and protein expression data confirmed the up-regulation of histone methyltransferases (SETDB1 and SETDB2) which contribute to the accumulation of H3K9me3 concomitantly in the different cancer types. Genome-wide studies suggest that transcriptional repression of genes is due to concordant loss of H3K4me3 and regional increment of H3K9me3. Conversely, genome-wide CpG site-specific DNA methylation showed no common changes at the IDTC state. This suggests that distinct histone methylation patterns rather than DNA methylation are driving the transition from parental to IDTCs. In addition, silencing of SETDB1/2 reversed multi drug tolerance. Alterations of histone marks in early multi-drug tolerance with an increment in H3K9me3 and loss of H3K4me3/H3K27me3 is neither exclusive for any particular stress response nor cancer type specific but rather a generic response.
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Emran et al. (2017) studied this question.