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

Abdullah Al Emran, Diego M. Marzese, Dinoop Ravindran Menon, Mitchell S. Stark, Joachim Torrano, Heinz Hammerlindl, Gao Zhang, Patricia Brafford, Matthew P. Salomon, Nellie Nelson, Sabrina Hammerlindl, Deepesh Gupta, Gordon Mills, Yiling Lu, Richard A. Sturm, Keith Flaherty, S. B.Hoon Dave, Brian Gabrielli, Meenhard Herlyn, Helmut Schaider

Research output: Contribution to journalArticle

10 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)8206-8222
Number of pages17
JournalOncotarget
Volume9
Issue number9
DOIs
StatePublished - Jan 1 2018
Externally publishedYes

Fingerprint

Histone Code
Drug Tolerance
Pharmaceutical Preparations
Neoplasms
DNA Methylation
Epigenomics
Genome
Holidays
Starvation
Drug Resistance
Histones
Colonic Neoplasms
Methylation
Melanoma
Lung Neoplasms
Up-Regulation

Keywords

  • Acquired drug resistance
  • Dna methylation
  • Epigenetic reprogramming
  • Histone modification
  • Stress-induced resistance

ASJC Scopus subject areas

  • Oncology

Cite this

Emran, A. A., Marzese, D. M., Menon, D. R., Stark, M. S., Torrano, J., Hammerlindl, H., ... Schaider, H. (2018). Distinct histone modifications denote early stress-induced drug tolerance in cancer. Oncotarget, 9(9), 8206-8222. https://doi.org/10.18632/oncotarget.23654

Distinct histone modifications denote early stress-induced drug tolerance in cancer. / Emran, Abdullah Al; Marzese, Diego M.; Menon, Dinoop Ravindran; Stark, Mitchell S.; Torrano, Joachim; Hammerlindl, Heinz; Zhang, Gao; Brafford, Patricia; Salomon, Matthew P.; Nelson, Nellie; Hammerlindl, Sabrina; Gupta, Deepesh; Mills, Gordon; Lu, Yiling; Sturm, Richard A.; Flaherty, Keith; Dave, S. B.Hoon; Gabrielli, Brian; Herlyn, Meenhard; Schaider, Helmut.

In: Oncotarget, Vol. 9, No. 9, 01.01.2018, p. 8206-8222.

Research output: Contribution to journalArticle

Emran, AA, Marzese, DM, Menon, DR, Stark, MS, Torrano, J, Hammerlindl, H, Zhang, G, Brafford, P, Salomon, MP, Nelson, N, Hammerlindl, S, Gupta, D, Mills, G, Lu, Y, Sturm, RA, Flaherty, K, Dave, SBH, Gabrielli, B, Herlyn, M & Schaider, H 2018, 'Distinct histone modifications denote early stress-induced drug tolerance in cancer', Oncotarget, vol. 9, no. 9, pp. 8206-8222. https://doi.org/10.18632/oncotarget.23654
Emran AA, Marzese DM, Menon DR, Stark MS, Torrano J, Hammerlindl H et al. Distinct histone modifications denote early stress-induced drug tolerance in cancer. Oncotarget. 2018 Jan 1;9(9):8206-8222. https://doi.org/10.18632/oncotarget.23654
Emran, Abdullah Al ; Marzese, Diego M. ; Menon, Dinoop Ravindran ; Stark, Mitchell S. ; Torrano, Joachim ; Hammerlindl, Heinz ; Zhang, Gao ; Brafford, Patricia ; Salomon, Matthew P. ; Nelson, Nellie ; Hammerlindl, Sabrina ; Gupta, Deepesh ; Mills, Gordon ; Lu, Yiling ; Sturm, Richard A. ; Flaherty, Keith ; Dave, S. B.Hoon ; Gabrielli, Brian ; Herlyn, Meenhard ; Schaider, Helmut. / Distinct histone modifications denote early stress-induced drug tolerance in cancer. In: Oncotarget. 2018 ; Vol. 9, No. 9. pp. 8206-8222.
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