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

  1. Utz Herbiga,e,1
  1. aNew Jersey Medical School-Cancer Center, Rutgers Biomedical and Health Sciences, Newark, NJ 07103;
  2. bDepartment of Pathology and Laboratory Medicine, New Jersey Medical School, Rutgers Biomedical and Health Sciences, Newark, NJ 07103;
  3. cNuclear Organization and Oncogenesis Unit, Department of Cell Biology and Infection, Institut Pasteur, 75015 Paris, France;
  4. dINSERM U993, F-75015 Paris, France;
  5. eDepartment of Microbiology, Biochemistry, and Molecular Genetics, Rutgers Biomedical and Health Sciences, Rutgers University, Newark, NJ 07103

  1. Edited by Victoria Lundblad, Salk Institute for Biological Studies, La Jolla, CA, and approved June 27, 2016 (received for review February 11, 2016)

Significance

Normal cells respond to oncogenic signals by activating cellular senescence, a state of irreversible/permanent growth arrest that prevents cells from undergoing further cell divisions. Although this oncogene-induced senescence (OIS) is considered a critical tumor-suppressive mechanism, the irreversible nature of OIS remains controversial. In this study, we demonstrate that OIS is not always stable. After a prolonged period in senescence, cells can re-enter the cell-division cycle with epigenetic changes that facilitate cell transformation. Escape from OIS was promoted by derepression of hTERT gene expression, an enzyme that provides cellular immortality and is activated in >90% of human cancers.

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.

Footnotes

  • ↵1To whom correspondence should be addressed. Email: herbigut{at}njms.rutgers.edu.

  • Author contributions: U.H. designed research; P.L.P. performed research; A.S., N.M., and O.B. contributed new reagents/analytic tools; P.L.P. analyzed data; and P.L.P. and U.H. wrote the paper.

  • The authors declare no conflict of interest.

  • This article is a PNAS Direct Submission.

  • This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1602379113/-/DCSupplemental.

Freely available online through the PNAS open access option.

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