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.

Sperm-specific COX6B2 enhances oxidative phosphorylation, proliferation, and survival in human lung adenocarcinoma

“…Cells were seeded at a density of 50,000 cells (HCC515) or 5000 cells (H2122) per 12-well plate and treated as previously described ( Gallegos et al, 2019 ). After 3 weeks, colonies were stained overnight with 0.01% crystal violet.…”

Role of immunotherapy in Ewing sarcoma

“…These data indicated that EWS-FLI1 directly activates the expression of the CT antigen FATE1 as a means of supporting ES sarcoma tumor cell survival. 93 Performing a database homology search CT antigen XAGE-1 was found to be expressed in ES. 94 Later, Liu et al found XAGE-1 to be expressed in 7/8 ES cell lines and in 4/9 ES patient samples.…”

“…As explained previously, ES is characterized by a pathognomonic chromosomal translocation that generates the EWS–FLI1 chimeric transcription factor; however, the transcriptional targets of EWS–FLI1 that are essential for tumorigenicity are incompletely defined. In a very recent study, Gallegos et al 93 found that EWS–FLI1 modulates the expression of a certain class of immunogenic tumor-associated genes, so-called cancer-testis (CT) antigens. Among CT antigens, the expression of which is typically restricted to germ cells and cancer cells, fetal and adult testis expressed 1 (FATE1) was found to be the most robustly induced in ES.…”

“…These data indicated that EWS–FLI1 directly activates the expression of the CT antigen FATE1 as a means of supporting ES sarcoma tumor cell survival. 93 …”

Cancer-testis Antigen FATE1 Expression in Adrenocortical Tumors Is Associated with A Pervasive Autoimmune Response and Is A Marker of Malignancy in Adult, but Not Children, ACC

“…FATE1 is expressed at high levels in about 40% of adult ACC and its expression is significantly and inversely correlated with patients' overall survival (OS) [5]. Additionally, FATE1 silencing increased sensitivity of the NCI-H1155 non-small lung cancer cell line to paclitaxel [6] and reduced viability of a variety of other cancer cell lines [7,8].…”