FOXR2 Is an Epigenetically Regulated Pan-Cancer Oncogene That Activates ETS Transcriptional Circuits.
FOXR2 Is an Epigenetically Regulated Pan-Cancer Oncogene That Activates ETS Transcriptional Circuits.
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DOI：
10.1158/0008-5472.can-22-0671
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发表时间：
2022-09-02
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影响因子：
11.2
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中科院分区：
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这项工作确定了一种新的启动子，驱动异常FOXR 2表达，并描绘FOXR 2作为一个泛癌癌基因，特异性激活ETS转录电路在人类癌症。 叉头框R2（FOXR2）是位于X染色体上的叉头转录因子，其表达通常限于睾丸。在这项研究中，我们对超过10，000个成人和儿童癌症样本进行了FOXR 2激活的泛癌症分析，发现FOXR 2在70%的所有癌症类型和8%的所有个体肿瘤中异常上调。大多数肿瘤（78%）通过先前未描述的表观遗传机制异常表达FOXR 2，该机制涉及新启动子的低甲基化，这在功能上被验证为FOXR 2表达癌细胞中FOXR 2表达和增殖所必需。FOXR2促进了多种癌症谱系的肿瘤生长，并在癌症中共同选择了ETS家族转录回路。总之，这项研究将FOXR 2确定为一种有效且普遍存在的癌基因，在大多数人类癌症中表观遗传学激活。FOXR 2劫持ETS转录电路的鉴定扩展了已知的激活ETS转录因子的机制，并突出了转录因子家族如何合作以增强肿瘤发生。这项工作确定了一种新的启动子，驱动异常FOXR 2表达，并描绘FOXR 2作为一个泛癌癌基因，特异性激活ETS转录电路在人类癌症。 参见Liu和Northcott的相关评论，第2977页
This work identifies a novel promoter that drives aberrant FOXR2 expression and delineates FOXR2 as a pan-cancer oncogene that specifically activates ETS transcriptional circuits across human cancers. Forkhead box R2 (FOXR2) is a forkhead transcription factor located on the X chromosome whose expression is normally restricted to the testis. In this study, we performed a pan-cancer analysis of FOXR2 activation across more than 10,000 adult and pediatric cancer samples and found FOXR2 to be aberrantly upregulated in 70% of all cancer types and 8% of all individual tumors. The majority of tumors (78%) aberrantly expressed FOXR2 through a previously undescribed epigenetic mechanism that involves hypomethylation of a novel promoter, which was functionally validated as necessary for FOXR2 expression and proliferation in FOXR2-expressing cancer cells. FOXR2 promoted tumor growth across multiple cancer lineages and co-opted ETS family transcription circuits across cancers. Taken together, this study identifies FOXR2 as a potent and ubiquitous oncogene that is epigenetically activated across the majority of human cancers. The identification of hijacking of ETS transcription circuits by FOXR2 extends the mechanisms known to active ETS transcription factors and highlights how transcription factor families cooperate to enhance tumorigenesis. This work identifies a novel promoter that drives aberrant FOXR2 expression and delineates FOXR2 as a pan-cancer oncogene that specifically activates ETS transcriptional circuits across human cancers. See related commentary by Liu and Northcott, p. 2977