Role of polycomb group proteins in stem cell self-renewal and cancer.

Molecular Oncology Laboratory, Cancer Research UK, London Research Institute, London, United Kingdom.
DNA and Cell Biology (Impact Factor: 1.99). 03/2005; 24(2):117-25. DOI: 10.1089/dna.2005.24.117
Source: PubMed

ABSTRACT Polycomb group proteins (PcG) form part of a gene regulatory mechanism that determines cell fate during normal and pathogenic development. The mechanism relies on epigenetic modifications on specific histone tails that are inherited through cell divisions, thus behaving de facto as a cellular memory. This cellular memory governs key events in organismal development as well as contributing to the control of normal cell growth and differentiation. Consequently, the dysregulation of PcG genes, such as Bmi1, Pc2, Cbx7, and EZH2 has been linked with the aberrant proliferation of cancer cells. Furthermore, at least three PcG genes, Bmi1, Rae28, and Mel18, appear to regulate self-renewal of specific stem cell types suggesting a link between the maintenance of cellular homeostasis and tumorigenesis. In this review, we will briefly summarize current views on PcG function and the evidence linking specific PcG proteins with the behavior of stem cells and cancer cells.

  • Source
  • [Show abstract] [Hide abstract]
    ABSTRACT: Osteosarcoma (OS) is an aggressive and highly metastatic form of primary bone cancer affecting young children and adults. Previous studies have shown that hypomethylation of critical genes is driving metastasis. Here, we examine whether hypermethylation treatment can block OS growth and pulmonary metastasis. Human OS cells LM-7 and MG-63 were treated with the ubiquitous methyl donor S-adenosylmethionine (SAM) or its inactive analog S-adenosylhomocystine (SAH) as control. Treatment with SAM resulted in a dose-dependent inhibition of tumor cell proliferation, invasion, cell migration, and cell cycle characteristics. Inoculation of cells treated with 150 μmol/L SAM for 6 days into tibia or via intravenous route into Fox Chase severe combined immune deficient (SCID) mice resulted in the development of significantly smaller skeletal lesions and a marked reduction in pulmonary metastasis as compared to control groups. Epigenome wide association studies (EWAS) showed differential methylation of several genes involved in OS progression and prominent signaling pathways implicated in bone formation, wound healing, and tumor progression in SAM-treated LM-7 cells. Real-time polymerase chain reaction (qPCR) analysis confirmed that SAM treatment blocked the expression of several prometastatic genes and additional genes identified by EWAS analysis. Immunohistochemical analysis of normal human bone and tissue array from OS patients showed significantly high levels of expression of one of the identified gene platelet-derived growth factor alpha (PDGFA). These studies provide a possible mechanism for the role of DNA demethylation in the development and metastasis of OS to provide a rationale for the use of hypermethylation therapy for OS patients and identify new targets for monitoring OS development and progression.
    Cancer Medicine 01/2015; DOI:10.1002/cam4.386
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The lamins are nuclear envelope proteins and main constituent of nuclear lamina surrounding the internal membrane of nuclear envelope. The lamina is the scaffold for nuclear envelope architecture and a framework composed of intermediate filament proteins such as type A and B lamins. Type A lamins (lamin A/C) are encoded by LMNA gene and are at the center of several biological functions essential for cells. Several studies have shown that mutations in LMNA gene are responsible for laminophathies associated with abnormalities in skeletal muscle, in heart, in adipose tissue, bone tissue and neuronal tissue. Lamin A and lamin C are synthesized from the differential splicing of the same messenger RNA but they have different type of maturations. The mutations in LMNA gene affect more often the maturation of lamin A and most of the physiological pathologies are linked to the absence of functional lamin A. Lamin A is a biomarker of differentiated cells and its synthesis is stimulated by vitamin A in embryonic stem cells. The suppressions of lamin A in vivo by endogen épigénétique modifications or in vitro by the interference RNA (iRNA) techniques or enzymatic degradations, reveal the central role of lamin A in the regulation of genes involved in cell division, DNA replication, DNA repair, gene transcription, chromatin organization, cell metabolism, sensitivity to insulin, cell motility, cell signaling, and cell immunity. Epithelial cell that had lost the capacity to express functional lamin A are frequently transformed in cancerous cells while adipose cells that had lost functional lamin A also lack the capacity to metabolize lipids and become resistant to insulin. In this review we emphasize the molecular mechanism involved in cancer genesis, in insulin-resistance and diabetes when the expression of lamin A is altered or lost as well as methods to restore lamins A/C expression.