Potential of DNMT and its Epigenetic Regulation for Lung Cancer Therapy

Abstract

Lung cancer, the leading cause of mortality in both men and women in the United States, is largely diagnosed at its advanced stages that there are no effective therapeutic alternatives. Although tobacco smoking is the well established cause of lung cancer, the underlying mechanism for lung tumorigenesis remains poorly understood. An important event in tumor development appears to be the epigenetic alterations, especially the change of DNA methylation patterns, which induce the most tumor suppressor gene silence. In one scenario, DNA methyltransferase (DNMT) that is responsible for DNA methylation accounts for the major epigenetic maintenance and alternation. In another scenario, DNMT itself is regulated by the environment carcinogens (smoke), epigenetic and genetic information. DNMT not only plays a pivotal role in lung tumorigenesis, but also is a promising molecular bio-marker for early lung cancer diagnosis and therapy. Therefore the elucidation of the DNMT and its related epigenetic regulation in lung cancer is of great importance, which may expedite the overcome of lung cancer.

Lung development: orchestrating the generation and regeneration of a complex organ

“…Other reports suggest that changes in the orientation of cell division can alter the shape of the branching lung and drive extension of branching regions towards a source of mitogenic signals. For example, Ras/Sprouty activity, which acts downstream of Fgf signaling, regulates spindle pole orientation, and activation of Kras randomizes the direction of spindle pole formation leading to lack of directionality in epithelial cell proliferation in the developing lung (Tang et al, 2009). This leads to loss of new branch points associated with dilation of the developing airway epithelium, indicating that Fgf signaling plays an important role in regulating the orientation of cell division along the proximaldistal axis of the developing airways (Fig.…”

“…During pulmonary fibrosis, DNA methylation by Dnmt1 represses transcription of miR17~92, a microRNA cluster that regulates lung development (Dakhlallah et al, 2013). Likewise, Dnmt1 mediates the progression of lung cancer through methylation of various promoter regions (Tang et al, 2009;Dakhlallah et al, 2013). As is the case for HDACs and HATs, the roles for these epigenetic factors in disease states strongly suggests a role for these factors during development that will need to be determined in further studies.…”

“…Can be successfully resected using surgery. (Tang et al, 2009). This leads to loss of new branch points associated with dilation of the developing airway epithelium, indicating that Fgf signaling plays an important role in regulating the orientation of cell division along the proximaldistal axis of the developing airways (Fig.…”

Akciğer Kanserli Hastalarda Plazma DNA Metiltransferaz ve Metil-CpG’ye Bağlanan Protein Seviyelerinin Değerlendirilmesi

“…Ancak timin bazı normalde DNA da bulunan bir baz olduğu için tamir mekanizmalarından kaçar ve bu şekilde oluşan nokta mutasyonlarının kanser gelişimini tetiklediği belirtilmiştir [5,16]. Kanser gelişimini birçok şekilde etkileyebilen DNA metilasyonu ile ilişkili enzim ve protein ekspresyonları akut miyeloid lösemi [17], akciğer [18,19], göğüs [20,21], kolorektal ve mide [22] TARTIŞMA DNA'nın metilasyonu, DNA metiltransferaz enzimleri tarafından katalizlenir ve metil bağlanma proteinleri yardımıyla gerçekleşir [1,11]. Gen ekspresyonu değişikliklerine bağlı olarak DNA metiltransferaz ve MBD proteinlerin seviyelerinde meydana gelen değişiklikler akut miyeloid lösemide [17], akciğer [18,19], göğüs [20,21], kolorektal ve mide [22] kanserlerinin de içinde bulunduğu birçok kanser tipinde rapor edilmiştir.…”

Silibinin Synergizes with Histone Deacetylase and DNA Methyltransferase Inhibitors in Upregulating E-cadherin Expression Together with Inhibition of Migration and Invasion of Human Non-small Cell Lung Cancer Cells

“…HDACs act in concert with other chromatin modifying enzymes, particularly DNMTs that methylate the gene promoter regions; E-cadherin has been reported to undergo methylation in ∼18% of the NSCLC tumor samples, as well as in NSCLC cell lines including H1299 (Zochbauer-Muller et al, 2001;Shames et al, 2006;Tang et al, 2009). Furthermore, loss of E-cadherin is an important parameter associated with resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) therapy.…”