Tobacco Smoke Induces Polycomb-Mediated Repression of Dickkopf-1 in Lung Cancer Cells
Thoracic Oncology Section, Surgery Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland 20892-1201, USA. Cancer Research
(Impact Factor: 9.33).
05/2009; 69(8):3570-8. DOI: 10.1158/0008-5472.CAN-08-2807
Limited information is available about epigenetic mechanisms by which cigarette smoke enhances the initiation and progression of lung cancer. To examine this issue, A549 and Calu-6 lung cancer cells were cultured in normal media with or without tobacco smoke condensate (TSC) under clinically relevant exposure conditions. Ten-day TSC exposure dramatically increased the tumorigenicity of lung cancer cells in nude mice. Microarray and quantitative reverse transcription-PCR (RT-PCR) experiments revealed that this phenomenon coincided with diminished expression of Dickkopf-1 (Dkk-1). Western blot, chromatin immunoprecipitation, methylation-specific PCR, and pyrosequencing experiments showed that repression of Dkk-1 coincided with decreased H4K16Ac, increased H3K27me3, and recruitment of SirT1, EZH2, SUZ12, and Bmi1 without DNA hypermethylation within the Dkk-1 promoter despite prolonged TSC exposures. Removal of TSC from culture media resulted in loss of promoter-associated polycomb repressor complexes and reexpression of Dkk-1. siRNA-mediated knockdown of EZH2 and SirT1 partially abrogated TSC-mediated inhibition of Dkk-1 expression. Western blot and quantitative RT-PCR array experiments showed that TSC exposure as well as knockdown of Dkk-1 activated Wnt signaling and significantly up-regulated Wnt5a in lung cancer cells. Knockdown of Dkk-1 recapitulated the dramatic protumorigenic effects of TSC exposure in Calu-6 cells. Despite the transient nature of Dkk-1 repression following TSC exposure in vitro, Dkk-1 remained silenced in tumor xenografts derived from TSC-treated Calu-6 cells. Collectively, these data provide evidence that cigarette smoke directly engages polycomb machinery to activate a signaling network implicated in maintenance of cancer stem cells.
Available from: Alejandro Lomniczi
- "In addition, SIRT1 promotes methylation of histone 3 at lysine 9 (H3K9me3) Vaquero and Reinberg, 2009, a modification associated with gene silencing (Wang et al., 2008; Ruthenburg et al., 2007; Guttman et al., 2009; Schaefer et al., 2009). SIRT1 interacts with the PcG complex to silence genes (Furuyama et al., 2004; Chopra and Mishra, 2005; Hussain et al., 2009; Pruitt et al., 2006; O'Hagan et al., 2011), is activated in the hypothalamus by decreased nutrient availability (Cakir et al., 2009; Dietrich et al., 2010; Ramadori et al., 2008), and is abundant in the ARC (Cakir et al., 2009; Dietrich et al., 2010; Ramadori et al., 2008). These considerations suggest that SIRT1 either by itself or in collaboration with the PcG complex may serve as an epigenetic link between energy balance and reproductive function. "
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ABSTRACT: Substantial progress has been made in recent years towards deciphering the molecular and genetic underpinnings of the pubertal process. The availability of powerful new methods to interrogate the human genome has led to the identification of genes that are essential for puberty to occur. Evidence has also emerged suggesting that the initiation of puberty requires the coordinated activity of gene sets organized into functional networks. At a cellular level, it is currently thought that loss of transsynaptic inhibition, accompanied by an increase in excitatory inputs, results in the pubertal activation of GnRH release. This concept notwithstanding, a mechanism of epigenetic repression targeting genes required for the pubertal activation of GnRH neurons was recently identified as a core component of the molecular machinery underlying the central restraint of puberty. In this chapter we will discuss the potential contribution of various mechanisms of epigenetic regulation to the hypothalamic control of female puberty.
Frontiers in Neuroendocrinology 08/2014; 36. DOI:10.1016/j.yfrne.2014.08.003 · 7.04 Impact Factor
Available from: Kevin Pruitt
- "While some mouse models have suggested that SIRT1 may promote genetic stability and suppress context-dependent tumorigenesis , the oncogenic contribution of SIRT1 has been demonstrated in diverse contexts. For example, SIRT1 has been shown to participate in silencing tumor suppressor genes , , stabilization of Dishevelled and β-catenin , promotion of cell migration –, aromatase expression , estrogen receptor signaling  and chemoresistance to conventional chemotherapeutic agents ,  "
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ABSTRACT: The Wnt signaling pathway is often chronically activated in diverse human tumors, and the Frizzled (FZD) family of receptors for Wnt ligands, are central to propagating oncogenic signals in a β-catenin-dependent and independent manner. SIRT1 is a class III histone deacetylase (HDAC) that deacetylates histone and non-histone proteins to regulate gene transcription and protein function. We previously demonstrated that SIRT1 loss of function led to a significant decrease in the levels of Dishevelled (Dvl) proteins. To further explore this connection between the sirtuins and components of the Wnt pathway, we analyzed sirtuin-mediated regulation of FZD proteins. Here we explore the contribution of sirtuin deacetylases in promoting constitutive Wnt pathway activation in breast cancer cells. We demonstrate that the use of small molecule inhibitors of SIRT1 and SIRT2, and siRNA specific to SIRT1, all reduce the levels of FZD7 mRNA. We further demonstrate that pharmacologic inhibition of SIRT1/2 causes a marked reduction in FZD7 protein levels. Additionally, we show that β-catenin and c-Jun occupy the 7 kb region upstream of the transcription start site of the FZD7 gene, and SIRT1 inhibition leads to a reduction in the occupancy of both β-catenin and c-Jun at points along this region. This work uncovers a new mechanism for the regulation of FZD7 and provides a critical new link between the sirtuins and FZD7, one of the earliest nodal points from which oncogenic Wnt signaling emanates. This study shows that inhibition of specific sirtuins may provide a unique strategy for inhibiting the constitutively active Wnt pathway at the level of the receptor.
PLoS ONE 06/2014; 9(6):e98861. DOI:10.1371/journal.pone.0098861 · 3.23 Impact Factor
Available from: Michal Wozniak
- "PRC1 in turn recognizes the methylated lysine and mediates transcriptional repression of selected genes. Aberrant expression of BMI-1 (PRC1 complex element) or Suz12 (PRC2 complex element) are documented in many different types of cancer and cancer stem cells   . "
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ABSTRACT: Current therapies against metastatic tumors are still ineffective. Cancer stem cells — a small subset of cells inside the tumor that possesses a self-renewal capacity — might be responsible for the recurrence of the tumor after anti-cancer therapies. Their immortality and unique drug resistance impede their eradication during therapy. The ‘stemness’ of these cells is controlled by microRNAs. These molecules possess the ability to downregulate gene expression by binding to the target mRNA. It turns out that microRNAs control the expression of approximately 60% of the genes in human cells. MicroRNA aberrant expression can lead to cancer development and progression. Therefore, recent research has focused on unraveling the role of microRNA in maintaining a stem-like phenotype in malignant tumors and cancer stem cells. This review summarizes our current knowledge about microRNAs that control the self-renewal capacity of cancer stem cells and indicates the importance of profound research aimed at developing efficient miRNA-targeted therapies.
Central European Journal of Biology 10/2013; 8(10). DOI:10.2478/s11535-013-0222-9 · 0.71 Impact Factor
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