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

doi:10.1016/j.xgen.2023.100293

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

Robert Wood Johnson Medical School (RWJMS), Pharmacology

Rutgers, The State University

Research output: Contribution to journal › Article › peer-review

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 language	English (US)
Article number	100293
Journal	Cell Genomics
Volume	3
Issue number	4
DOIs	https://doi.org/10.1016/j.xgen.2023.100293
State	Published - 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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10.1016/j.xgen.2023.100293

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Martínez-Zamudio, R. I., Stefa, A., Nabuco Leva Ferreira Freitas, J. A., Vasilopoulos, T., Simpson, M., Doré, G., Roux, P. F., Galan, M. A., Chokshi, R. J., Bischof, O., & Herbig, U. (2023). Escape from oncogene-induced senescence is controlled by POU2F2 and memorized by chromatin scars. Cell Genomics, 3(4), Article 100293. https://doi.org/10.1016/j.xgen.2023.100293

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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.",

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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",

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year = "2023",

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doi = "10.1016/j.xgen.2023.100293",

language = "English (US)",

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AU - Martínez-Zamudio, Ricardo Iván

AU - Stefa, Alketa

AU - Nabuco Leva Ferreira Freitas, José Américo

AU - Vasilopoulos, Themistoklis

AU - Simpson, Mark

AU - Doré, Gregory

AU - Roux, Pierre François

AU - Galan, Mark A.

AU - Chokshi, Ravi J.

AU - Bischof, Oliver

AU - Herbig, Utz

PY - 2023/4/12

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N2 - 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.

AB - 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.

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

Abstract

All Science Journal Classification (ASJC) codes

Keywords

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