Promyelocytic leukemia protein regulates angiogenesis and epithelial–mesenchymal transition to limit metastasis in MDA‐MB‐231 breast cancer cells

Abstract

Promyelocytic leukemia protein (PML) modulates diverse cell functions that contribute to both tumor suppressor and pro‐oncogenic effects, depending on the cellular context. We show here that PML knockdown (KD) in MDA‐MB‐231, but not MCF7, breast cancer cells, prolonged stem‐cell‐like survival, and increased cell proliferation and migration, which is in line with gene‐enrichment results from their RNA sequencing analysis. Of note, increased migration was accompanied by higher levels of the epithelial–mesenchymal transition (EMT) regulator Twist‐related protein 2 (TWIST2). We showed here that PML binds to TWIST2 via its basic helix–loop–helix (bHLH) region and functionally interferes with the suppression of the epithelial target of TWIST2, CD24. In addition, PML ablation in MDA‐MB‐231 cells led to higher protein levels of hypoxia‐inducible factor 1‐alpha (HIF1a), resulting in a higher cell hypoxic response. Functionally, PML directly suppressed the induction of the HIF1a target gene vascular endothelial growth factor A (VEGFa). In line with these results, tumor xenografts of MDA‐MB‐231 PML‐KD cells had enhanced aggressive properties, including higher microvessel density, faster local growth, and higher metastatic ability, with a preference for lung. Collectively, PML suppresses the cancer aggressive behavior by multiple mechanisms that impede both the HIF–hypoxia–angiogenic and EMT pathways.