期刊
MOLECULAR AND CELLULAR BIOLOGY
卷 39, 期 14, 页码 -出版社
AMER SOC MICROBIOLOGY
DOI: 10.1128/MCB.00138-19
关键词
BNIP3L; CT antigen; cancer/testis antigen; EWSR1-FLI1; Ewing sarcoma; FATE1; RNF183
资金
- NIH Mechanisms of Diseases and Translational Science (MoDTS) [T32GM109776-02]
- NSF GRFP training grant [2016219621]
- NCI [R01CA166447, P30CA016086]
- Corn-Hammond Fund for Childhood Cancer Research
- V Foundation for Cancer Research
- Rita Allen Foundation
- Stand Up to Cancer [IRG1211]
- National Cancer Institute [CA196905]
- One Million 4 Anna Foundation
- St. Baldrick's Foundation
- Simmons Cancer Center Support Grant [5P30 CA142543-05]
- Pipers Legacy
- NIH [T32GM007062]
- [T32GM007040-37]
- [F30CA183464]
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.
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