Over-Expression of LSD1 Promotes Proliferation, Migration and Invasion in Non-Small Cell Lung Cancer

Background: Lysine specific demethylase 1 (LSD1) has been identified and biochemically characterized in epigenetics, but the pathological roles of its dysfunction in lung cancer remain to be elucidated. The aim of this study was to evaluate the prognostic significance of LSD1 expression in patients with non-small cell lung cancer (NSCLC) and to define its exact role in lung cancer proliferation, migration and invasion. Methods: The protein levels of LSD1 in surgically resected samples from NSCLC patients were detected by immunohistochemistry or Western blotting. The mRNA levels of LSD1 were detected by qRT-PCR. The correlation of LSD1 expression with clinical characteristics and prognosis was determined by statistical analysis. Cell proliferation rate was assessed by MTS assay and immunofluorescence. Cell migration and invasion were detected by scratch test, matrigel assay and transwell invasion assay. Results: LSD1 expression was higher in lung cancer tissue more than in normal lung tissue. Our results showed that overexpression of LSD1 protein were associated with shorter overall survival of NSCLC patients. LSD1 was localized mainly to the cancer cell nucleus. Interruption of LSD1 using siRNA or a chemical inhibitor, pargyline, suppressed proliferation, migration and invasion of A549, H460 and 293T cells. Meanwhile, over-expression of LSD1 enhanced cell growth. Finally, LSD1 was shown to regulate epithelial-to-mesenchymal transition in lung cancer cells

KDM1A microenvironment, its oncogenic potential, and therapeutic significance

The lysine-specific histone demethylase 1A (KDM1A) was the first demethylase to challenge the concept of the irreversible nature of methylation marks. KDM1A, containing a flavin adenine dinucleotide (FAD)-dependent amine oxidase domain, demethylates histone 3 lysine 4 and histone 3 lysine 9 (H3K4me1/2 and H3K9me1/2). It has emerged as an epigenetic developmental regulator and was shown to be involved in carcinogenesis. The functional diversity of KDM1A originates from its complex structure and interactions with transcription factors, promoters, enhancers, oncoproteins, and tumor-associated genes (tumor suppressors and activators). In this review, we discuss the microenvironment of KDM1A in cancer progression that enables this protein to activate or repress target gene expression, thus making it an important epigenetic modifier that regulates the growth and differentiation potential of cells. A detailed analysis of the mechanisms underlying the interactions between KDM1A and the associated complexes will help to improve our understanding of epigenetic regulation, which may enable the discovery of more effective anticancer drugs

Epigenetic modulators as therapeutic targets in prostate cancer

Prostate cancer is one of the most common non-cutaneous malignancies among men worldwide. Epigenetic aberrations, including changes in DNA methylation patterns and/or histone modifications, are key drivers of prostate carcinogenesis. These epigenetic defects might be due to deregulated function and/or expression of the epigenetic machinery, affecting the expression of several important genes. Remarkably, epigenetic modifications are reversible and numerous compounds that target the epigenetic enzymes and regulatory proteins were reported to be effective in cancer growth control. In fact, some of these drugs are already being tested in clinical trials. This review discusses the most important epigenetic alterations in prostate cancer, highlighting the role of epigenetic modulating compounds in pre-clinical and clinical trials as potential therapeutic agents for prostate cancer management.info:eu-repo/semantics/publishedVersio

Genetic Alterations and Changes in Expression of Histone Demethylases in Prostate Cancer

BACKGROUND. Historic demethylases LSD1, JHDM2A, and GASC1 have been suggested to function as androgen receptor co-activators, and to be involved in prostate cancer (PC) progression. We aim to identify genetic alterations and changes in expression of these genes in PC. METHODS. PC cell lines, xenografts as well as clinical specimens were screened for mutations using denaturating high-performance liquid chromatography and sequencing, and for expression alterations by using quantitative RT-PCR and immunohistochemistry. RESULTS. Only known single nucleotide polymorphisms, but no mutations, were found in these genes. JHDMA2 mRNA expression was slightly increased (P<0.05) in PC compared with benign prostate hyperplasia (BPH), whereas the expression of GASC1 was slightly higher (P < 0.05) in castration-resistant PC (CRPC) compared with untreated PC or BPH. The m RNA expression of LSD1 was not altered in PC. The expression of LSD1 protein was somewhat, although not statistically significantly (P=0.0521) lower in CRPC compared with untreated PC. In prostatectomy specimens, the level of LSD1 protein expression was associated with low pT-stage (P=0.0402), but not with Gleason score or progression-free survival. CONCLUSIONS. As no genetic alterations and only very modest expression changes were found, it is unlikely that LSD1, JHDM2A, or GASC1 play a major role in the progression of PC. Prostate 70: 889-898, 2010. (C) 2010 Wiley-Liss, Inc