Estrogen-related receptor alpha (ERRα) promotes gastrointestinal stromal tumor progression and epithelial-mesenchymal...

Gastrointestinal stromal tumor (GIST) is the most common human sarcoma and primarily driven by a gain-of-function mutation in either the KIT or PDGFRA receptor tyrosine kinase. Estrogen-related receptor alpha (ERRα, encoded by ESRRA) is an orphan nuclear receptor that shares structural homology and overlapping transcriptional targets with estrogen receptor alpha (ERα). We found that ERRα was highly expressed in human GIST cell lines and human GIST surgical specimens. Pharmacologic inhibition of ERRα using the inverse agonist XCT790 or siRNA-mediated knockdown of ERRα reduced viability, colony formation, and migration of human GIST cell lines. Furthermore, XCT790 suppressed the growth of established tumor xenografts. ERRα knockdown in GIST T1 cells reduced Hallmark Epithelial-Mesenchymal Transition (EMT) by gene set enrichment analysis of RNA-seq data and β-catenin was identified as a key differentially expressed gene. Lastly, ERRα co-immunoprecipitated with nuclear β-catenin and ERRα knockdown decreased levels of active nuclear β-catenin. Thus, ERRα promotes tumor progression and EMT in GIST, revealing a novel molecular pathway and potential therapeutic target.