Distinct histone modifications denote early stress-induced drug tolerance in cancer.

Autor:	Emran AA; Dermatology Research Centre, The University of Queensland Diamantina Institute, The University of Queensland, Translational Research Institute, Brisbane, Australia., Marzese DM; Department of Translational Molecular Medicine, John Wayne Cancer Institute, Santa Monica, CA, USA., Menon DR; Dermatology Research Centre, The University of Queensland Diamantina Institute, The University of Queensland, Translational Research Institute, Brisbane, Australia., Stark MS; Dermatology Research Centre, The University of Queensland Diamantina Institute, The University of Queensland, Translational Research Institute, Brisbane, Australia., Torrano J; Dermatology Research Centre, The University of Queensland Diamantina Institute, The University of Queensland, Translational Research Institute, Brisbane, Australia., Hammerlindl H; Dermatology Research Centre, The University of Queensland Diamantina Institute, The University of Queensland, Translational Research Institute, Brisbane, Australia., Zhang G; The Wistar Institute, Philadelphia, PA, USA., Brafford P; The Wistar Institute, Philadelphia, PA, USA., Salomon MP; Department of Translational Molecular Medicine, John Wayne Cancer Institute, Santa Monica, CA, USA., Nelson N; Sequencing Center, John Wayne Cancer Institute, Santa Monica, CA, USA., Hammerlindl S; Dermatology Research Centre, The University of Queensland Diamantina Institute, The University of Queensland, Translational Research Institute, Brisbane, Australia., Gupta D; Dermatology Research Centre, The University of Queensland Diamantina Institute, The University of Queensland, Translational Research Institute, Brisbane, Australia., Mills GB; MD Anderson Centre, Houston, TX, USA., Lu Y; MD Anderson Centre, Houston, TX, USA., Sturm RA; Dermatology Research Centre, The University of Queensland Diamantina Institute, The University of Queensland, Translational Research Institute, Brisbane, Australia., Flaherty K; Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA., Hoon DSB; Department of Translational Molecular Medicine, John Wayne Cancer Institute, Santa Monica, CA, USA., Gabrielli B; Mater Research Institute, Translational Research Institute, The University of Queensland, Woolloongabba, Queensland, Australia., Herlyn M; The Wistar Institute, Philadelphia, PA, USA., Schaider H; Dermatology Research Centre, The University of Queensland Diamantina Institute, The University of Queensland, Translational Research Institute, Brisbane, Australia.
Jazyk:	angličtina
Zdroj:	Oncotarget [Oncotarget] 2017 Dec 24; Vol. 9 (9), pp. 8206-8222. Date of Electronic Publication: 2017 Dec 24 (Print Publication: 2018).
DOI:	10.18632/oncotarget.23654
Abstrakt:	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. Competing Interests: CONFLICTS OF INTEREST Gordon B. Mills serves as a consultant for AstraZeneca, Blend Therapeutics, Critical Outcome Technologies Inc., HanAl Bio Korea, Illumina, Nuevolution, Pfizer, Provista Diagnostics, Roche, Signal Chem Lifesciences, Symphogen, Tau Therapeutics; owns stock in Catena Pharmaceuticals, PTV Healthcare Capital, Spindle Top Capital; and has received research funding from Adelson Medical Research Foundation, AstraZeneca, Critical Outcome Technologies Inc., GSK, and Illumina.
Databáze:	MEDLINE
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