飞行1
癌症研究
下调和上调
转移
融合基因
基因
肉瘤
生物
表型
转录因子
癌症
医学
遗传学
病理
作者
Connor J. Hughes,Kaiah M. Fields,Etienne Danis,Jessica Y. Hsu,Deepika Neelakantan,Melanie Y. Vincent,Annika Gustafson,Michael Oliphant,Varsha Sreekanth,Vadym Zaberezhnyy,James C. Costello,Paul Jedlicka,Heide L. Ford
标识
DOI:10.1038/s41467-023-39945-w
摘要
Abstract Ewing sarcoma (ES), which is characterized by the presence of oncogenic fusion proteins such as EWS/FLI1, is an aggressive pediatric malignancy with a high rate of early dissemination and poor outcome after distant spread. Here we demonstrate that the SIX1 homeoprotein, which enhances metastasis in most tumor types, suppresses ES metastasis by co-regulating EWS/FLI1 target genes. Like EWS/FLI1, SIX1 promotes cell growth/transformation, yet dramatically inhibits migration and invasion, as well as metastasis in vivo. We show that EWS/FLI1 promotes SIX1 protein expression, and that the two proteins share genome-wide binding profiles and transcriptional regulatory targets, including many metastasis-associated genes such as integrins, which they co-regulate. We further show that SIX1 downregulation of integrins is critical to its ability to inhibit invasion, a key characteristic of metastatic cells. These data demonstrate an unexpected anti-metastatic function for SIX1, through coordinate gene regulation with the key oncoprotein in ES, EWS/FLI1.
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