Search

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.

The multitasking promyelocytic leukemia (PML) protein was originally recognized as a tumor‐suppressive factor, but more recent evidence has implicated PML in tumor cell prosurvival actions and poor patient prognosis in specific cancer settings. Here, we report that inducible PMLIV expression inhibits cell proliferation as well as self‐renewal and impairs cell cycle progression of breast cancer cell lines in a reversible manner. Transcriptomic profiling identified a large number of PML‐deregulated genes associated with various cell processes. Among them, cell cycle‐ and division‐related genes and their cognitive regulators are highly ranked. In this study, we focused on previously unknown PML targets, namely the Forkhead transcription factors. PML suppresses the Forkhead box subclass M1 (FOXM1) transcription factor at both the RNA and protein levels, along with many of its gene targets. We show that FOXM1 interacts with PMLIV primarily via its DNA‐binding domain and dynamically colocalizes in PML nuclear bodies. In parallel, PML modulates the activity of Forkhead box O3 (FOXO3), a factor opposing certain FOXM1 activities, to promote cell survival and stress resistance. Thus, PMLIV affects the balance of FOXO3 and FOXM1 transcriptional programs by acting on discrete gene subsets to favor both growth inhibition and survival. Interestingly, PMLIV‐specific knockdown mimicked ectopic expression vis‐à‐vis loss of proliferative ability and self‐renewal, but also led to loss of survival ability as shown by increased apoptosis. We propose that divergent or similar effects on cell physiology may be elicited by high or low PMLIV levels dictated by other concurrent genetic or epigenetic cancer cell states that may additionally account for its disparate effects in various cancer types.