Derepression of hTERT gene expression promotes escape from oncogene-induced cellular senescence

Priyanka L. Patel, Anitha Suram, Neena Mirani, Oliver Bischof, Utz Herbig

Research output: Contribution to journalArticle

29 Citations (Scopus)

Abstract

Oncogene-induced senescence (OIS) is a critical tumor-suppressing mechanism that restrains cancer progression at premalignant stages, in part by causing telomere dysfunction. Currently it is unknown whether this proliferative arrest presents a stable and therefore irreversible barrier to cancer progression. Here we demonstrate that cells frequently escape OIS induced by oncogenic H-Ras and B-Raf, after a prolonged period in the senescence arrested state. Cells that had escaped senescence displayed high oncogene expression levels, retained functional DNA damage responses, and acquired chromatin changes that promoted c-Myc-dependent expression of the human telomerase reverse transcriptase gene (hTERT). Telomerase was able to resolve existing telomeric DNA damage response foci and suppressed formation of new ones that were generated as a consequence of DNA replication stress and oncogenic signals. Inhibition of MAP kinase signaling, suppressing c-Myc expression, or inhibiting telomerase activity, caused telomere dysfunction and proliferative defects in cells that had escaped senescence, whereas ectopic expression of hTERT facilitated OIS escape. In human early neoplastic skin and breast tissue, hTERT expression was detected in cells that displayed features of senescence, suggesting that reactivation of telomerase expression in senescent cells is an early event during cancer progression in humans. Together, our data demonstrate that cells arrested in OIS retain the potential to escape senescence by mechanisms that involve derepression of hTERT expression.

Original languageEnglish (US)
Pages (from-to)E5024-E5033
JournalProceedings of the National Academy of Sciences of the United States of America
Volume113
Issue number34
DOIs
StatePublished - Aug 23 2016

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Cell Aging
Oncogenes
Gene Expression
Genes
Telomerase
Telomere
DNA Damage
Neoplasms
human TERT protein
DNA Replication
Chromatin
Breast
Phosphotransferases
Skin

All Science Journal Classification (ASJC) codes

  • General

Cite this

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title = "Derepression of hTERT gene expression promotes escape from oncogene-induced cellular senescence",
abstract = "Oncogene-induced senescence (OIS) is a critical tumor-suppressing mechanism that restrains cancer progression at premalignant stages, in part by causing telomere dysfunction. Currently it is unknown whether this proliferative arrest presents a stable and therefore irreversible barrier to cancer progression. Here we demonstrate that cells frequently escape OIS induced by oncogenic H-Ras and B-Raf, after a prolonged period in the senescence arrested state. Cells that had escaped senescence displayed high oncogene expression levels, retained functional DNA damage responses, and acquired chromatin changes that promoted c-Myc-dependent expression of the human telomerase reverse transcriptase gene (hTERT). Telomerase was able to resolve existing telomeric DNA damage response foci and suppressed formation of new ones that were generated as a consequence of DNA replication stress and oncogenic signals. Inhibition of MAP kinase signaling, suppressing c-Myc expression, or inhibiting telomerase activity, caused telomere dysfunction and proliferative defects in cells that had escaped senescence, whereas ectopic expression of hTERT facilitated OIS escape. In human early neoplastic skin and breast tissue, hTERT expression was detected in cells that displayed features of senescence, suggesting that reactivation of telomerase expression in senescent cells is an early event during cancer progression in humans. Together, our data demonstrate that cells arrested in OIS retain the potential to escape senescence by mechanisms that involve derepression of hTERT expression.",
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Derepression of hTERT gene expression promotes escape from oncogene-induced cellular senescence. / Patel, Priyanka L.; Suram, Anitha; Mirani, Neena; Bischof, Oliver; Herbig, Utz.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 113, No. 34, 23.08.2016, p. E5024-E5033.

Research output: Contribution to journalArticle

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