Upregulation of the Mevalonate Pathway through EWSR1-FLI1/EGR2 Regulatory Axis Confers Ewing Cells Exquisite Sensitivity to Statins.

ABSTRACT: Ewing sarcoma (EwS) is an aggressive primary bone cancer in children and young adults characterized by oncogenic fusions between genes encoding FET-RNA-binding proteins and ETS transcription factors, the most frequent fusion being EWSR1-FLI1. We show that EGR2, an Ewing-susceptibility gene and an essential direct target of EWSR1-FLI1, directly regulates the transcription of genes encoding key enzymes of the mevalonate (MVA) pathway. Consequently, Ewing sarcoma is one of the tumors that expresses the highest levels of mevalonate pathway genes. Moreover, genome-wide screens indicate that MVA pathway genes constitute major dependencies of Ewing cells. Accordingly, the statin inhibitors of HMG-CoA-reductase, a rate-limiting enzyme of the MVA pathway, demonstrate cytotoxicity in EwS. Statins in

SUBMITTER: Buchou C 

PROVIDER: S-EPMC9100622 | biostudies-literature | 2022 May

REPOSITORIES: biostudies-literature