Promyelocytic leukemia protein (PML) controls breast cancer cell proliferation by modulating Forkhead transcription factors

Abstract

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 ( FOXM 1) transcription factor at both the RNA and protein levels, along with many of its gene targets. We show that FOXM 1 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 ( FOXO 3), a factor opposing certain FOXM 1 activities, to promote cell survival and stress resistance. Thus, PMLIV affects the balance of FOXO 3 and FOXM 1 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.

PML Differentially Regulates Growth and Invasion in Brain Cancer

“…The only condition that spheroid formation was facilitated was by the addition of an ECM-like substrate within the hanging-drop, which has been previously suggested to improve cellular aggregation and formation of 3D structures [33,34]. These findings are in line with previous work that reported the inhibitory role of PML IV in cell proliferation and 3D sphere formation of a breast cancer model [28].…”

“…In this work, we genetically modified the U87MG GB cell line to conditionally overexpress the PML IV protein. PML IV is the most well-studied isoform and it has been previously identified as a strong growth suppressor in various systems [28][29][30]. However, the role of PML IV in the pathophysiology of GB regarding both the proliferative and infiltrative nature of the disease is still not clear.…”

FOXO transcription factor family in cancer and metastasis

“…In support of a tumoursuppressive role for FOXO acetylation, a report shows that the acetylation recruits FOXO1 to promyelocytic leukaemia (PML) protein in the nucleus to protect FOXO1 against ubiquitination and to promote its activity in pancreatic beta cells [198]. In agreement, the interaction between FOXO3 and PML has also been observed in breast cancer [199]. In addition, another study shows that four-and-a-half LIM 2 (FHL2) interacts with FOXO1 to facilitate SIRT1-mediated deacetylation to reduce FOXO1 activity in prostate cancer [188].…”

Hypertriglyceridemia in Newly Diagnosed Acute Promyelocytic Leukemia

“…This inactivation leads to decreased gluconeogenesis and the release of very low-density lipoprotein by the liver after feeding. FOXO1 stimulates microsomal triglyceride transfer protein and apolipoprotein C-III, which lead to the activation of particle assembly and inhibition of lipoprotein lipase, the two -which are both causes of increased plasma TG (45). Interestingly, the retinoid effects on FOXO1-dependent increases in apolipoprotein C-III are inhibited by PPARg (46).…”