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

08:00 EDT 30th March 2019 | BioPortfolio

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

The multitasking Promyelocytic leukemia (PML) protein was originally recognized as a tumor suppressive factor, but more recent evidence has implicated PML in tumor cell pro-survival 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 level, along with many of its gene targets. We show that FOXM1 interacts with PMLIV primarily via its DNA binding domain and dynamically co-localizes in PML nuclear bodies. In parallel, PML modulates the activity of 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 favour 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.


Journal Details

This article was published in the following journal.

Name: Molecular oncology
ISSN: 1878-0261


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Medical and Biotech [MESH] Definitions

A Krupple-type transcription factor consisting of an N-terminal BTB DOMAIN and nine CYS2-HIS2 ZINC FINGERS. It localizes to the nucleus and regulates cell cycle progression and gene expression for tissue development and homeostasis; it may also function as an epigenetic regulator through its interactions with HISTONE DEACETYLASE. Genetic rearrangements involving the ZBTB16 gene are associated with ACUTE PROMYELOCYTIC LEUKEMIA.

A tripartite motif protein that contains three ZINC FINGERS, including a RING FINGER DOMAIN, at its N-terminal. Several nuclear and one cytoplasmic isoforms result from alternative splicing of the PML gene; most nuclear isoforms localize to subnuclear structures (PML nuclear bodies) that are disrupted in ACUTE PROMYELOCYTIC LEUKEMIA cells.

Nuclear phosphoprotein encoded by the p53 gene (GENES, P53) whose normal function is to control CELL PROLIFERATION and APOPTOSIS. A mutant or absent p53 protein has been found in LEUKEMIA; OSTEOSARCOMA; LUNG CANCER; and COLORECTAL CANCER.

The phosphoprotein encoded by the BRCA1 gene (GENE, BRCA1). In normal cells the BRCA1 protein is localized in the nucleus, whereas in the majority of breast cancer cell lines and in malignant pleural effusions from breast cancer patients, it is localized mainly in the cytoplasm. (Science 1995;270(5237):713,789-91)

A promyelocytic cell line derived from a patient with ACUTE PROMYELOCYTIC LEUKEMIA. HL-60 cells lack specific markers for LYMPHOID CELLS but express surface receptors for FC FRAGMENTS and COMPLEMENT SYSTEM PROTEINS. They also exhibit phagocytic activity and responsiveness to chemotactic stimuli. (From Hay et al., American Type Culture Collection, 7th ed, pp127-8)

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