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

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. [Display omitted] •Oncogene-induced senescence is unstable•POU2F2 is necessary for escape from oncogene-induced senescence•Post-senescent cells are marked by senescence-associated chromatin scars (SACSs)•SACS and POU2F2 gene signatures have diagnostic and prognostic potential in CRC Increasing evidence suggests that oncogene-induced senescence (OIS) is an unstable barrier to malignant cancer progression. Martínez-Zamudio et al. characterize the transcription factor network that promotes OIS escape and identify an epigenetic memory of OIS in post-senescent cells with diagnostic and prognostic potential.