Lysyl Oxidase Is Induced by Cell Density-Mediated Cell Cycle Suppression via RB-E2F1-HIF-1α Axis

Remodeling of the matrix surrounding tumor cells plays a crucial role in the development and maintenance of cancer. Lysyl oxidase (LOX), a matrix remodeling factor, is induced by HIF-1 alpha under hypoxic conditions and associated with tumor growth and metastasis. Here, we report that high cell density induces HIF-1 alpha expression under normoxic condition, resulting in the promotion of LOX expression. This phenomenon was observed in the retinoblastoma tumor suppressor (RB)-proficient breast cancer cells but not in RB-deficient cells. In RB-proficient cancer cells, the cell cycle regulator E2F1 was down-regulated and cell cycle progression was inhibited at high density culture condition. Knockdown of E2F1 stabilized HIF-1 alpha and promoted LOX expression, while knockdown of both E2F1 and HIF-1 alpha prevented the up-regulation of LOX. These findings suggest that elevated cell density enhances cell cycle arrest and matrix remodeling via RB-E2F1-HIF-1 alpha axis.