The ETS Transcription Factor ETV6 Constrains the Transcriptional Activity of EWS-FLI to Promote Ewing Sarcoma

Overview

Journal Nat Cell Biol

Specialty Cell Biology

Date 2023 Jan 19

PMID 36658220

Authors

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

Affiliations

Soon will be listed here.

Abstract

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.

Citing Articles

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