Transcriptional repression of SOX2 by p53 in cancer cells regulates cell identity and migration

IF 4.7 2区 医学 Q1 ONCOLOGY
Patricia Lado-Fernández, Jéssica M. Vilas, Tânia Fernandes, Carmen Carneiro, Sabela Da Silva-Álvarez, Valentín Estévez-Souto, Pablo Pedrosa, Miguel González-Barcia, Luis E. Abatti, Jennifer A. Mitchell, Carmen Rivas, Gema Moreno-Bueno, Anxo Vidal, Manuel Collado
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Abstract

During cancer development and progression, many genetic alterations lead to the acquisition of novel features that confer selective advantage to cancer cells and that resemble developmental programs. SRY-box transcription factor 2 (SOX2) is one of the key pluripotency transcription factors, expressed during embryonic development and active in adult stem cells. In cancer, SOX2 is frequently dysregulated and associated with tumor stemness and poor patient survival. SOX2 expression is suppressed in differentiated cells by tumor suppressor proteins that form a transcriptional repressive complex. We previously identified some of these proteins and found that their absence combined with deficiency in Trp53 leads to maximal dysregulated expression of Sox2. Using cancer cell lines of different origin and with different p53 status, we show here that manipulating TP53 to restore or decrease its activity results in repression or induction of SOX2, respectively. Mechanistically, we observed that the regulation of SOX2 expression by TP53 is transcriptional and identified Trp53 bound to the promoter region and the Sox2 Regulatory Region 2 enhancer of Sox2. Forcing high levels of SOX2 in cancer cells leads to morphological changes that molecularly correspond to the acquisition of a more mesenchymal phenotype, correlating with an increased migratory capacity. Finally, the analysis of human breast cancer samples shows that this correlation between TP53 status, levels of expression of SOX2, and a more metastatic phenotype is also observed in cancer patients. Our results support the notion that lack of TP53 in tumor cells results in deregulated expression of developmental gene SOX2 with phenotypic consequences related to increased malignization.

Abstract Image

肿瘤细胞中p53对SOX2的转录抑制调节细胞身份和迁移。
在癌症的发展和进展过程中,许多遗传改变导致获得新的特征,赋予癌细胞选择优势,类似于发育程序。SRY-box转录因子2 (SOX2)是关键的多能性转录因子之一,在胚胎发育过程中表达,在成体干细胞中活跃。在癌症中,SOX2经常失调,与肿瘤干性和患者生存率低有关。SOX2的表达在分化细胞中被肿瘤抑制蛋白抑制,肿瘤抑制蛋白形成转录抑制复合体。我们之前鉴定了其中的一些蛋白,发现它们的缺失加上Trp53的缺失导致Sox2的最大程度失调表达。使用不同来源和不同p53状态的癌细胞系,我们在这里表明,操纵TP53恢复或降低其活性分别导致SOX2的抑制或诱导。在机制上,我们观察到TP53对SOX2表达的调控是转录性的,并鉴定出Trp53结合到SOX2的启动子区和SOX2的调控区2增强子上。在癌细胞中强制高水平的SOX2导致形态变化,这在分子上对应于获得更多的间充质表型,与迁移能力增加相关。最后,对人类乳腺癌样本的分析表明,在癌症患者中也观察到TP53状态、SOX2表达水平和转移性更强的表型之间的相关性。我们的研究结果支持这样一种观点,即肿瘤细胞中缺乏TP53会导致发育基因SOX2的表达失调,从而导致与恶性肿瘤增加相关的表型后果。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
CiteScore
13.40
自引率
3.10%
发文量
460
审稿时长
2 months
期刊介绍: The International Journal of Cancer (IJC) is the official journal of the Union for International Cancer Control—UICC; it appears twice a month. IJC invites submission of manuscripts under a broad scope of topics relevant to experimental and clinical cancer research and publishes original Research Articles and Short Reports under the following categories: -Cancer Epidemiology- Cancer Genetics and Epigenetics- Infectious Causes of Cancer- Innovative Tools and Methods- Molecular Cancer Biology- Tumor Immunology and Microenvironment- Tumor Markers and Signatures- Cancer Therapy and Prevention
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