ETS转录因子ETV6限制EWS-FLI的转录活性，促进Ewing肉瘤。
The ETS transcription factor ETV6 constrains the transcriptional activity of EWS-FLI to promote Ewing sarcoma.
发表日期：2023 Feb
作者：
Diana Y Lu, Jana M Ellegast, Kenneth N Ross, Clare F Malone, Shan Lin, Nathaniel W Mabe, Neekesh V Dharia, Ashleigh Meyer, Amy Conway, Angela H Su, Julia Selich-Anderson, Cenny Taslim, Andrea K Byrum, Bo Kyung A Seong, Biniam Adane, Nathanael S Gray, Miguel N Rivera, Stephen L Lessnick, Kimberly Stegmaier
来源：
NATURE CELL BIOLOGY
摘要：
转录因子（TF）常常在癌症中发生突变。儿科肿瘤全基因组变异较少，但TFs经常携带影响，提供了精确研究支持突变TF驱动致癌的转录电路的背景。一个广泛相关的机制引起了强烈关注，涉及突变TF能够劫持野生型特异性TF进行自我强化的转录电路的能力。然而，尚不知道这种特定类型的电路在所有突变TF驱动的癌症中是否同样关键。在这里，我们描述了一种促进Ewing肉瘤的另一个但核心的转录机制，其中对融合TF EWS-FLI活动的限制有助于支持癌症生长，而不是强化。我们发现ETV6是这种疾病的关键TF依赖性，因为它具有反直觉的作用，能够抑制EWS-FLI的转录输出。这项工作发现了一个以前未描述的促进癌症的转录机制。©2023。作者。
Transcription factors (TFs) are frequently mutated in cancer. Paediatric cancers exhibit few mutations genome-wide but frequently harbour sentinel mutations that affect TFs, which provides a context to precisely study the transcriptional circuits that support mutant TF-driven oncogenesis. A broadly relevant mechanism that has garnered intense focus involves the ability of mutant TFs to hijack wild-type lineage-specific TFs in self-reinforcing transcriptional circuits. However, it is not known whether this specific type of circuitry is equally crucial in all mutant TF-driven cancers. Here we describe an alternative yet central transcriptional mechanism that promotes Ewing sarcoma, wherein constraint, rather than reinforcement, of the activity of the fusion TF EWS-FLI supports cancer growth. We discover that ETV6 is a crucial TF dependency that is specific to this disease because it, counter-intuitively, represses the transcriptional output of EWS-FLI. This work discovers a previously undescribed transcriptional mechanism that promotes cancer.© 2023. The Author(s).