PDF(Pubmed)
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.
摘要：
尽管癌基因诱导的衰老（OIS）是一种有效的肿瘤抑制机制，最近的研究表明，细胞可以从OIS中逃脱，具有转化细胞的特征。然而,促进OIS逃逸的机制仍不清楚，人类癌症中衰老后细胞的证据缺失。这里,我们使用动态多维分析来解开OIS逃逸的调节机制。我们证明了AP1和POU2F2转录因子在逃避OIS中的关键作用，并将衰老相关染色质疤痕（SACSs）鉴定为在结直肠癌进展过程中可检测到的OIS的表观遗传记忆。POU2F2水平在癌前病变中已经升高，并且随着细胞从OIS逃逸，其表达和与顺式调节元件的结合活性与患者生存率降低有关。我们的结果支持一个模型，其中POU2F2利用衰老逃逸所必需的预编码增强子景观，并揭示POU2F2和SACS基因特征作为具有诊断和预后潜力的有价值的生物标志物。
