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.
FOXO3 is a tumour suppressor that orchestrates the expression of genes that regulate cell cycle progression, apoptosis, metabolism, oxidative stress and other important cellular processes. Its inactivation is closely associated with tumorigenesis and cancer progression. On the other hand, Sirtuin proteins have been demonstrated to be able to deacetylate and thus, causing FOXO3 inactivation at the post-translational level. Therefore, targeting sirtuin proteins renders new avenues for breast cancer treatment. Here, we describe three procedures for studying FOXO3 post-translational modifications controlled by sirtuin proteins in cancer cells.
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