Screening for DAX1/EWS-FLI1 functional inhibitors identified dihydroorotate dehydrogenase as a therapeutic target for Ewing's sarcoma.

ABSTRACT:

Objective

EWS-FLI1 is the most common oncogenic fusion protein in Ewing's sarcoma family tumors (ESFTs). DAX1, an orphan member of the nuclear receptor superfamily, is up-regulated by EWS-FLI1 and plays a key role in the transformed phenotype of ESFTs.

Methods

To discover a functional inhibitor of DAX1 and EWS-FLI1, we screened small-molecular inhibitors using a DAX1 reporter assay system.

Results

K-234 and its derivatives, which were dihydroorotate dehydrogenase (DHODH) inhibitors, showed inhibitory effects in the reporter assay. K-234 inhibited the growth of Ewing's sarcoma with various fusion types, and K-234 derivatives altered the expression of EWS-FLI1-regulated genes. The DAX1 expression had no effect on the growth inhibitory effect of the K-234 derivatives, while DHODH overexpression or uridine treatment attenuated their inhibitory effects, suggesting that inhibition by K-234 derivatives occurs through DHODH inhibition. An in vivo study showed that a K-234 derivative clearly inhibited tumor growth in an Ewing's sarcoma xenograft mouse model.

Conclusion

Taken together, the present results suggest that DHODH inhibitors can inhibit the function of DAX1/EWS-FLI1 in ESFTs and might be a therapeutic agent with potent anti-tumor activity for Ewing's sarcoma patients.

SUBMITTER: Watanabe M 

PROVIDER: S-EPMC10166890 | biostudies-literature | 2023 Apr

REPOSITORIES: biostudies-literature