@article{0373c8114fb34e16bbf3de22f2cfe7b8,
title = "Escape from oncogene-induced senescence is controlled by POU2F2 and memorized by chromatin scars",
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.",
keywords = "AP-1, OIS, OIS escape, Oct-2, POU2F2, SACS, cellular senescence, colorectal cancer, oncogene-induced senescence, senescence-associated chromatin scars",
author = "Mart{\'i}nez-Zamudio, {Ricardo Iv{\'a}n} and Alketa Stefa and {Nabuco Leva Ferreira Freitas}, {Jos{\'e} Am{\'e}rico} and Themistoklis Vasilopoulos and Mark Simpson and Gregory Dor{\'e} and Roux, {Pierre Fran{\c c}ois} and Galan, {Mark A.} and Chokshi, {Ravi J.} and Oliver Bischof and Utz Herbig",
note = "Funding Information: R.I.M.-Z. is a Mexican National Researchers System (SNI) fellow. This study was supported by the National Cancer Institute of the NIH ( R01CA136533 ). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health . Funding Information: R.I.M.-Z. is a Mexican National Researchers System (SNI) fellow. This study was supported by the National Cancer Institute of the NIH (R01CA136533). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. R.I.M.-Z. A.S. O.B. and U.H. designed the study, designed experiments, interpreted data, and wrote the manuscript. R.I.M.-Z. and A.S. generated cell culture systems; performed ChIP-seq, ATAC-seq, and RNA interference experiments; and analyzed data. R.I.M.-Z. performed computational analyses on the microarray, ChIP-seq, ATAC-seq, ENCODE, GEO, and TCGA data and generated and prepared figures. P.-F.R. processed ATAC-seq data and designed computational pipelines to analyze microarray and ChIP-seq data. A.S. performed colony formation and telomerase activity experiments and analyzed data. A.S. and T.V. performed EdU incorporation and TIF experiments and analyzed data. M.S. performed immunohistochemistry experiments. G.D. generated the microarray data. J.A.N.L.F.F. generated the TF networks and analyzed ATAC-seq data. R.J.C. conducted surgeries on cancer patients, and R.J.C. and M.A.G. provided tumor tissue and consulted on pathologic diagnoses. The authors declare no competing interests. Publisher Copyright: {\textcopyright} 2023 The Authors",
year = "2023",
month = apr,
day = "12",
doi = "10.1016/j.xgen.2023.100293",
language = "English (US)",
volume = "3",
journal = "Cell Genomics",
issn = "2666-979X",
publisher = "Cell Press",
number = "4",
}