@article{dc7a3a5d666c4b24b653994baa3e4b93,
title = "EWSR1-FLI1 activation of the cancer/testis antigen FATE1 promotes Ewing sarcoma survival",
abstract = "Ewing sarcoma is characterized by a pathognomonic chromosomal translocation that generates the EWSR1-FLI1 chimeric transcription factor. The transcriptional targets of EWSR1-FLI1 that are essential for tumorigenicity are incompletely defined. Here, we found that EWSR1-FLI1 modulates the expression of cancer/testis (CT) antigen genes, whose expression is biased to the testes but is also activated in cancer. Among these CT antigens, fetal and adult testis expressed 1 (FATE1) is most robustly induced. EWSR1-FLI1 associates with the GGAA repeats in the proximal promoter of FATE1, which exhibits accessible chromatin exclusively in mesenchymal progenitor cells (MPCs) and Ewing sarcoma cells. Expression of EWSR1-FLI1 in non-Ewing sarcoma cells and in MPCs enhances FATE1 mRNA and protein expression. Conversely, depletion of EWSR1-FLI1 in Ewing sarcoma cells leads to a loss of FATE1 expression. Importantly, we found that FATE1 is required for survival and anchorage-independent growth in Ewing sarcoma cells via attenuating the accumulation of BNIP3L, a BH3-only protein that is toxic when stabilized. This action appears to be mediated by the E3 ligase RNF183. We propose that engaging FATE1 function can permit the bypass of cell death mechanisms that would otherwise inhibit tumor progression.",
keywords = "BNIP3L, CT antigen, Cancer/testis antigen, EWSR1-FLI1, Ewing sarcoma, FATE1, RNF183",
author = "Gallegos, {Zachary R.} and Patrick Taus and Gibbs, {Zane A.} and Kathleen McGlynn and Gomez, {Nicholas C.} and Ian Davis and Whitehurst, {Angelique W.}",
note = "Funding Information: Z.R.G. was supported by NIH Mechanisms of Diseases and Translational Science (MoDTS) training grant T32GM109776-02 and NSF GRFP training grant 2016219621. Z.A.G. was supported by pharmacology training grant NIH T32GM007062. P.T. was supported by general medicine training grants T32GM007040-37 and F30CA183464. I.D. was supported in part by the NCI (R01CA166447 and P30CA016086), the Corn-Hammond Fund for Childhood Cancer Research, the V Foundation for Cancer Research, and the Rita Allen Foundation. A.W.W. was supported in part by Stand Up to Cancer (IRG1211), the National Cancer Institute (CA196905), and grants from the One Million 4 Anna Foundation, Pipers Legacy, and St. Baldrick{\textquoteright}s Foundation. The Simmons Cancer Center Support Grant (5P30 CA142543-05) supported shared resources used in this study at UTSW. We have no conflicts of interest to disclose. Funding Information: Z.R.G. was supported by NIH Mechanisms of Diseases and Translational Science (MoDTS) training grant T32GM109776-02 and NSF GRFP training grant 2016219621. Z.A.G. was supported by pharmacology training grant NIH T32GM007062. P.T. was supported by general medicine training grants T32GM007040-37 and F30CA183464. I.D. was supported in part by the NCI (R01CA166447 and P30CA016086), the Corn-Hammond Fund for Childhood Cancer Research, the V Foundation for Cancer Research, and the Rita Allen Foundation. A.W.W. was supported in part by Stand Up to Cancer (IRG1211), the National Cancer Institute (CA196905), and grants from the One Million 4 Anna Foundation, Pipers Legacy, and St. Baldrick?s Foundation. The Simmons Cancer Center Support Grant (5P30 CA142543-05) supported shared resources used in this study at UTSW. Publisher Copyright: Copyright {\textcopyright} 2019 American Society for Microbiology. All Rights Reserved.",
year = "2019",
month = jul,
day = "1",
doi = "10.1128/MCB.00138-19",
language = "English (US)",
volume = "39",
journal = "Molecular and Cellular Biology",
issn = "0270-7306",
publisher = "American Society for Microbiology",
number = "14",
}