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

Angiosarcoma (AS) is a rare and aggressive tumor originating from vascular endothelial cells, characterized by a high metastatic rate and poor prognosis. 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. Additionally, we identified 465 common genes downregulated by ENX in both AS cell lines and upregulated in Dicer1 cKO tumors, enriched in pathways related to the cell cycle, angiogenesis, and migration. These genes are targeted by tumor-suppressive miRNAs—such as let-7, miR-155-5p, and miR-126a—highlighting miRNA-mediated regulation of key oncogenic processes in AS. Our results establish the essential role of miRNA biogenesis in suppressing AS and reveal a pharmacologically targetable vulnerability via ENX-mediated restoration of miRNA function.