Canonical microRNA loss drives tumor development implicating therapeutic efficacy of enoxacin in angiosarcoma.

Our prior work established that endothelial loss of Dicer1, a key enzyme in microRNA (miRNA) processing, drives AS formation in mice, suggesting a tumor suppressive role for miRNAs. Here, we validated this hypothesis by generating a novel conditional knockout model targeting Dgcr8, a core component of the microprocessor complex required for pri-miRNA processing.

Conditional deletion of Dgcr8 phenocopies Dicer1 loss, resulting in spontaneous AS formation and global loss of mature miRNAs. We further demonstrate that treatment with enoxacin (ENX)—a small molecule known to enhance miRNA processing—reduces viability, migration, and clonogenicity of AS cells. ENX increases the abundance of tumor-suppressive miRNAs and downregulates oncogenic pathways, including E2F targets and angiogenesis.