Escape from oncogene-induced senescence is controlled by POU2F2 and memorized by chromatin scars

Ricardo Iván Martínez-Zamudio, Alketa Stefa, José Américo Nabuco Leva Ferreira Freitas, Themistoklis Vasilopoulos, Mark Simpson, Gregory Doré, Pierre François Roux, Mark A. Galan, Ravi J. Chokshi, Oliver Bischof, Utz Herbig

Research output: Contribution to journalArticlepeer-review

10 Scopus citations

Abstract

Although oncogene-induced senescence (OIS) is a potent tumor-suppressor mechanism, recent studies revealed that cells could escape from OIS with features of transformed cells. However, the mechanisms that promote OIS escape remain unclear, and evidence of post-senescent cells in human cancers is missing. Here, we unravel the regulatory mechanisms underlying OIS escape using dynamic multidimensional profiling. We demonstrate a critical role for AP1 and POU2F2 transcription factors in escape from OIS and identify senescence-associated chromatin scars (SACSs) as an epigenetic memory of OIS detectable during colorectal cancer progression. POU2F2 levels are already elevated in precancerous lesions and as cells escape from OIS, and its expression and binding activity to cis-regulatory elements are associated with decreased patient survival. Our results support a model in which POU2F2 exploits a precoded enhancer landscape necessary for senescence escape and reveal POU2F2 and SACS gene signatures as valuable biomarkers with diagnostic and prognostic potential.

Original languageEnglish (US)
Article number100293
JournalCell Genomics
Volume3
Issue number4
DOIs
StatePublished - Apr 12 2023

All Science Journal Classification (ASJC) codes

  • Genetics
  • Biochemistry, Genetics and Molecular Biology (miscellaneous)

Keywords

  • AP-1
  • OIS
  • OIS escape
  • Oct-2
  • POU2F2
  • SACS
  • cellular senescence
  • colorectal cancer
  • oncogene-induced senescence
  • senescence-associated chromatin scars

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