Suppression of breast cancer progression by FBXL16 via oxygen-independent regulation of HIF1 alpha stability

초록

Triple-negative breast cancers (TNBCs) are characterized by high rates of recurrence and poor clinical outcomes. Deregulated E3 ligases are involved in breast cancer pathogenesis and progression, but the underlying mechanisms are unclear Here, we find that F-box and leucine-rich repeat protein 16 (FBXL16) acts as a tumor suppressor in TNBCs. FBXL16 directly binds to HIF1 alpha and induces its ubiquitination and degradation, regardless of the tumor microenvironment, resulting in blockade of the HIF1 alpha-mediated epithelial-mesenchymal transition (EMT) and angiogenesis features of breast cancer. In TNBCs, FBXL16 expression is downregulated by the p38/miR-135b-3p axis, and loss of FBXL16 expression restores HIF1 alpha-mediated metastatic features of breast cancer. Low expression of FBXL16 is associated with high-grade and lymph node-positive tumors and poor overall survival of breast cancer. Taken together, these findings demonstrate that modulation of FBXL16 expression may offer a favorable strategy for treatment of patients with metastatic breast cancer, including TNBCs.

키워드