KDM1A

Gene Summary

Gene:KDM1A; lysine (K)-specific demethylase 1A
Aliases: AOF2, KDM1, LSD1, BHC110
Location:1p36.12
Summary:This gene encodes a nuclear protein containing a SWIRM domain, a FAD-binding motif, and an amine oxidase domain. This protein is a component of several histone deacetylase complexes, though it silences genes by functioning as a histone demethylase. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Apr 2009]
Databases:OMIM, VEGA, HGNC, Ensembl, GeneCard, Gene
Protein:lysine-specific histone demethylase 1A
HPRD
Source:NCBIAccessed: 25 June, 2015

Ontology:

What does this gene/protein do?
Show (52)

Cancer Overview

Research Indicators

Publications Per Year (1990-2015)
Graph generated 25 June 2015 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • Western Blotting
  • Gene Silencing
  • Transcriptional Activation
  • Protein Structure, Tertiary
  • HEK293 Cells
  • RNA Interference
  • p53 Protein
  • Enzyme Inhibitors
  • DNA-Binding Proteins
  • Chromosome 1
  • MicroRNAs
  • Messenger RNA
  • Histones
  • Androgen Receptors
  • Mutation
  • Promoter Regions
  • Neoplasm Proteins
  • Immunohistochemistry
  • Transcription Factors
  • RTPCR
  • Methylation
  • Gene Expression Profiling
  • siRNA
  • Histone Demethylases
  • Cell Proliferation
  • Protein Binding
  • Pargyline
  • Co-Repressor Proteins
  • Chromatin
  • Cell Movement
  • Transcription
  • Androgens
  • Oligonucleotide Array Sequence Analysis
  • Apoptosis
  • KDM1A
  • Cancer Gene Expression Regulation
  • Prostate Cancer
  • Breast Cancer
  • DNA Methylation
  • Epigenetics
  • Oxidoreductases, N-Demethylating
Tag cloud generated 25 June, 2015 using data from PubMed, MeSH and CancerIndex

Specific Cancers (2)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: KDM1A (cancer-related)

Cortez V, Samayoa C, Zamora A, et al.
PELP1 overexpression in the mouse mammary gland results in the development of hyperplasia and carcinoma.
Cancer Res. 2014; 74(24):7395-405 [PubMed] Article available free on PMC after 15/12/2015 Related Publications
Estrogen receptor (ER) coregulator overexpression promotes carcinogenesis and/or progression of endocrine related-cancers in which steroid hormones are powerful mitogenic agents. Recent studies in our laboratory, as well as others, demonstrated that the estrogen receptor coregulator PELP1 is a proto-oncogene. PELP1 interactions with histone demethylase KDM1 play a critical role in its oncogenic functions and PELP1 is a prognostic indicator of decreased survival in patients with breast cancer. However, the in vivo significance of PELP1 deregulation during initiation and progression of breast cancer remains unknown. We generated an inducible, mammary gland-specific PELP1-expressing transgenic (Tg) mouse (MMTVrtTA-TetOPELP1). We found more proliferation, extensive side branching, and precocious differentiation in PELP1-overexpressing mammary glands than in control glands. Aged MMTVrtTA-TetOPELP1 Tg mice had hyperplasia and preneoplastic changes as early as 12 weeks, and ER-positive mammary tumors occurred at a latency of 14 to 16 months. Mechanistic studies revealed that PELP1 deregulation altered expression of a number of known ER target genes involved in cellular proliferation (cyclin D1, CDKs) and morphogenesis (EGFR, MMPs) and such changes facilitated altered mammary gland morphogenesis and tumor progression. Furthermore, PELP1 was hyper-phosphorylated at its CDK phosphorylation site, suggesting an autocrine loop involving the CDK-cyclin D1-PELP1 axis in promoting mammary tumorigenesis. Treatment of PELP1 Tg mice with a KDM1 inhibitor significantly reduced PELP1-driven hyperbranching, reversed alterations in cyclin D1 expression levels, and reduced CDK-driven PELP1 phosphorylation. These results further support the hypothesis that PELP1 deregulation has the potential to promote breast tumorigenesis in vivo and represent a novel model for future investigation into molecular mechanisms of PELP1-mediated tumorigenesis.

Theisen ER, Gajiwala S, Bearss J, et al.
Reversible inhibition of lysine specific demethylase 1 is a novel anti-tumor strategy for poorly differentiated endometrial carcinoma.
BMC Cancer. 2014; 14:752 [PubMed] Article available free on PMC after 15/12/2015 Related Publications
BACKGROUND: Endometrial cancer is the most common gynecologic malignancy. Type II endometrial carcinoma is often poorly differentiated and patients diagnosed with Type II disease (~11%) are disproportionately represented in annual endometrial cancer deaths (48%). Recent genomic studies highlight mutations in chromatin regulators as drivers in Type II endometrial carcinoma tumorigenesis, suggesting the use of epigenetic targeted therapies could provide clinical benefit to these patients. We investigated the anti-tumor efficacy of the LSD1 inhibitor HCI2509 in two poorly differentiated Type II endometrial cancer cell lines AN3CA and KLE.
METHODS: The effects of HCI2509 on viability, proliferation, anchorage-independent growth, global histone methylation, LSD1 target gene induction, cell cycle, caspase activation and TUNEL were assayed. KLE cells were used in an orthotopic xenograft model to assess the anti-tumor activity of HCI2509.
RESULTS: Both AN3CA and KLE cells were sensitive to HCI2509 treatment with IC50s near 500 nM for cell viability. Inhibition of LSD1 with HCI2509 caused decreased proliferation and anchorage independent growth in soft agar, elevated global histone methylation, and perturbed the cell cycle in both cell lines. These effects were largely dose-dependent. HCI2509 treatment also caused apoptotic cell death. Orthotopic implantation of KLE cells resulted in slow-growing and diffuse tumors throughout the abdomen. Tumor burden was distributed log-normally. Treatment with HCI2509 resulted 5/9 tumor regressions such that treatment and regressions were significantly associated (p=0.034).
CONCLUSIONS: Our findings demonstrate the anti-cancer properties of the LSD1 inhibitor HCI2509 on poorly differentiated endometrial carcinoma cell lines, AN3CA and KLE. HCI2509 showed single-agent efficacy in orthotopic xenograft studies. Continued studies are needed to preclinically validate LSD1 inhibition as a therapeutic strategy for endometrial carcinoma.

Di Santi A, Cernera G, Migliaccio A, Perillo B
Analysis of histone posttranslational modifications in the control of chromatin plasticity observed at estrogen-responsive sites in human breast cancer cells.
Methods Mol Biol. 2014; 1204:59-69 [PubMed] Related Publications
It is well established that histone posttranslational modifications mediate the control of gene expression played by chromatin. Such modifications are commonly reversible and many alternatives are open to drive transcription of inducible genes. Estrogens govern growth and survival of hormone-sensitive cells by inducing expression of genes important for cell cycle progression and apoptosis. Transcription of estrogen-responsive genes is triggered by the lysine-specific demethylase 1 (LSD1)-dependent demethylation of dimethylated lysine 9 in histone H3 (H3K9me2) that accompanies to local generation of oxygen reactive species (ROS). Production of ROS modifies guanines in neighbor DNA with consequent recruitment of base-excision repair (BER) enzymes and formation of breaks that support creation of bridges between sites that, although distant on linear DNA, establish strategic contacts useful for productive transcription.

Wu Y, Zhang L, Wang Y, et al.
Long noncoding RNA HOTAIR involvement in cancer.
Tumour Biol. 2014; 35(10):9531-8 [PubMed] Related Publications
Evidences have been provided that long noncoding RNAs (lncRNAs) act as key molecules in epigenetic regulation and are involved in the development process of cancer in recent studies. HOX transcript antisense RNA (HOTAIR), a long intergenic noncoding RNA (lincRNA), functions as a molecular scaffold to link and target two histone modification complexes PRC2 and LSD1, then reprograms chromatin states by couples histone H3K27 methylation and H3K4 demethylation for epigenetic gene silencing to promote cancer metastasis. HOTAIR, regarded as an oncogene, is pervasively overexpressed in most solid cancers and correlated with tumor invasion, progression, metastasis, and poor prognosis, and HOTAIR has been proven to play a critical role in most biological process of cancer and would be a potential new target in cancer therapy.

Derr RS, van Hoesel AQ, Benard A, et al.
High nuclear expression levels of histone-modifying enzymes LSD1, HDAC2 and SIRT1 in tumor cells correlate with decreased survival and increased relapse in breast cancer patients.
BMC Cancer. 2014; 14:604 [PubMed] Article available free on PMC after 15/12/2015 Related Publications
BACKGROUND: Breast cancer is a heterogeneous disease with a highly variable clinical outcome in which both genetic and epigenetic changes have critical roles. We investigated tumor expression levels of histone-modifying enzymes LSD1, HDAC2 and SIRT1 in relation with patient survival and tumor relapse in a retrospective cohort of 460 breast cancer patients. Additionally, we correlated expression levels with tumor differentiation and tumor cell proliferation.
METHODS: Immunohistochemical staining for LSD1, HDAC2 and SIRT1 was performed on tissue microarrays of tumor and corresponding normal formalin-fixed paraffin-embedded tissues from breast cancer patients. Median nuclear expression levels in tumor tissues were used to divide the patients into low and high expression categories. In combined expression analyses, patients were divided into four subgroups: 1, all enzymes below-median; 2, one enzyme above-median; 3, two enzymes above-median; 4, all three enzymes above-median. The Cox proportional hazard model was used for univariate and multivariate survival analyses. The Pearson Chi-square method was used to assess correlation of combined expression levels with tumor cell proliferation and tumor differentiation.
RESULTS: Expression of LSD1 and SIRT1, but not of HDAC2, was significantly increased in tumor tissues compared to their normal counterparts (both p < 0.001). Multivariate survival analyses identified SIRT1 as independent prognostic factor for relapse-free survival (RFS) with a hazard ratio (HR) of 1.34 (95% CI = 1.04-1.74, p = 0.02). For overall survival (OS), no significant differences were found when the individual enzymes were analyzed. Analyses of combined expression levels of the three histone-modifying enzymes correlated with OS (p = 0.03) and RFS (p = 0.006) with a HR of respectively 1.49 (95% CI = 1.07-2.08) and 1.68 (95% CI = 1.16-2.44) in multivariate analyses and were also related to tumor differentiation (p < 0.001) and tumor cell proliferation (p = 0.002).
CONCLUSIONS: When the combined expression levels were analyzed, high expression of LSD1, HDAC2 and SIRT1 showed shorter patient survival time and shorter time to tumor relapse and correlated with poor tumor differentiation and a high level of tumor cell proliferation. Expression of these histone-modifying enzymes might therefore be involved in breast cancer pathogenesis.

Hsu HC, Liu YS, Tseng KC, et al.
CBB1003, a lysine-specific demethylase 1 inhibitor, suppresses colorectal cancer cells growth through down-regulation of leucine-rich repeat-containing G-protein-coupled receptor 5 expression.
J Cancer Res Clin Oncol. 2015; 141(1):11-21 [PubMed] Related Publications
PURPOSE: Lysine-specific demethylase 1 (LSD1) was highly expressed in several malignancies and had been implicated in pathological processes of cancer cells. However, the role of LSD1 in colorectal cancer (CRC) carcinogenesis, prognosis and treatment remains uncharacterized.
METHODS: In this study, we examined LSD1 expression in paraffin-embedded CRC specimens from 295 patients, including 65 patients with paired samples of colorectal carcinoma, adjacent adenoma and normal colorectal tissues. Using an LSD1 inhibitor, CBB1003, as a probe, we studied the association between LSD1 and leucine-rich repeat-containing G-protein-coupled receptor 5 (LGR5), a CRC stem cell marker involved in carcinogenesis. The anti-tumor effects of CBB1003 on CRC cells were also examined.
RESULTS: LSD1 expression was significantly elevated in colorectal tumor tissues compared with adjacent adenoma and normal colorectal tissues (P < 0.001), and LSD1 levels were significantly correlated with an advanced AJCC T stage (P = 0.012) and distant metastasis (P = 0.004). CBB1003 inhibited CRC cell proliferation and colony formation. In cultured CRC cells, inhibiting LSD1 activity by CBB1003 caused a decrease in LGR5 levels while overexpression of LGR5 reduced CBB1003-induced cell death. We also observed the inactivation of β-catenin/TCF signaling after CBB1003 treatment, consistent with the positive correlations among LSD1, LGR5, β-catenin and c-Myc expression in human colon tumor and adenoma tissues.
CONCLUSION: Our result suggested that LSD1 overexpression promotes CRC development and that the LSD1 inhibitor inhibits CRC cell growth by down-regulating LGR5 levels and inactivates the Wnt/β-catenin pathway. Thus, LSD1 and its inhibitor might provide a new target or a useful strategy for therapy of CRC.

Mino K, Nishimura S, Ninomiya S, et al.
Regulation of tissue factor pathway inhibitor-2 (TFPI-2) expression by lysine-specific demethylase 1 and 2 (LSD1 and LSD2).
Biosci Biotechnol Biochem. 2014; 78(6):1010-7 [PubMed] Related Publications
Tissue factor pathway inhibitor-2 (TFPI-2) is a major inhibitor of extracellular matrix degradation. Decreases in TFPI-2 contribute to malignant tumor cell production, and TFPI-2 is a presumed tumor suppressor. TFPI-2 gene transcription is regulated by two epigenetic mechanisms: DNA methylation of the promoter and K4 methylation of histone 3 (H3). Lysine-specific demethylase 1 (LSD1) and LSD2 demethylate H3K4me2/1. LSD1 has been implicated in TFPI-2 regulation through both epigenetic mechanisms, but the involvement of LSD2 remains unknown. We prepared a monoclonal anti-LSD2 antibody that clearly distinguishes LSD2 from LSD1. Knockdown of LSD1 or LSD2 by siRNAs increased TFPI-2 protein and mRNA. Simultaneous knockdown of both LSD1 and LSD2 showed additive effects. Bisulfite sequencing revealed that CpG sites in the TFPI-2 promoter region were unmethylated. These results indicate that LSD2 also contributes to TFPI-2 regulation through histone modification, and that further studies of the involvement of LSD2 in tumor malignancy are warranted.

Cai B, Song XQ, Cai JP, Zhang S
HOTAIR: a cancer-related long non-coding RNA.
Neoplasma. 2014; 61(4):379-91 [PubMed] Related Publications
Long non-coding RNA was dismissed as merely transcriptional "noise" in the past decades. Numerous researches have shown that lncRNAs regulated gene expression at the epigenetic level. Moreover, lncRNAs played important roles in proliferation, apoptosis and invasiveness of tumor cells, and participated in metastatic capacity of cancers. Recent studies revealed HOX transcript antisense RNA, a lncRNA with regulatory functions of transcription, could bind PRC2 and LSD1/CoREST/REST complexes and direct to the specific gene sites, resulted in H3K27 methylation and H3K4 demethylation and ultimately gene silencing. Aberrant HOTAIR expression was associated with various sites of cancers such as breast, hepatocellular, gastric, colorectal, pancreatic et al; and affected survival and prognosis of cancer patients. In this review, we introduce an overall view of HOTAIR by describing the known molecular mechanisms and potential functions of HOTAIR and summarizing the latest progresses on the research of HOTAIR in various human cancers.

Han X, Gui B, Xiong C, et al.
Destabilizing LSD1 by Jade-2 promotes neurogenesis: an antibraking system in neural development.
Mol Cell. 2014; 55(3):482-94 [PubMed] Related Publications
Histone H3K4 demethylase LSD1 plays an important role in stem cell biology, especially in the maintenance of the silencing of differentiation genes. However, how the function of LSD1 is regulated and the differentiation genes are derepressed are not understood. Here, we report that elimination of LSD1 promotes embryonic stem cell (ESC) differentiation toward neural lineage. We showed that the destabilization of LSD1 occurs posttranscriptionally via the ubiquitin-proteasome pathway by an E3 ubiquitin ligase, Jade-2. We demonstrated that Jade-2 is a major LSD1 negative regulator during neurogenesis in vitro and in vivo in both mouse developing cerebral cortices and zebra fish embryos. Apparently, Jade-2-mediated degradation of LSD1 acts as an antibraking system and serves as a quick adaptive mechanism for re-establishing epigenetic landscape without more laborious transcriptional regulations. As a potential anticancer strategy, Jade-2-mediated LSD1 degradation could potentially be used in neuroblastoma cells to induce differentiation toward postmitotic neurons.

Phillips S, Prat A, Sedic M, et al.
Cell-state transitions regulated by SLUG are critical for tissue regeneration and tumor initiation.
Stem Cell Reports. 2014; 2(5):633-47 [PubMed] Article available free on PMC after 15/12/2015 Related Publications
Perturbations in stem cell activity and differentiation can lead to developmental defects and cancer. We use an approach involving a quantitative model of cell-state transitions in vitro to gain insights into how SLUG/SNAI2, a key developmental transcription factor, modulates mammary epithelial stem cell activity and differentiation in vivo. In the absence of SLUG, stem cells fail to transition into basal progenitor cells, while existing basal progenitor cells undergo luminal differentiation; together, these changes result in abnormal mammary architecture and defects in tissue function. Furthermore, we show that in the absence of SLUG, mammary stem cell activity necessary for tissue regeneration and cancer initiation is lost. Mechanistically, SLUG regulates differentiation and cellular plasticity by recruiting the chromatin modifier lysine-specific demethylase 1 (LSD1) to promoters of lineage-specific genes to repress transcription. Together, these results demonstrate that SLUG plays a dual role in repressing luminal epithelial differentiation while unlocking stem cell transitions necessary for tumorigenesis.

Fiskus W, Sharma S, Shah B, et al.
Highly effective combination of LSD1 (KDM1A) antagonist and pan-histone deacetylase inhibitor against human AML cells.
Leukemia. 2014; 28(11):2155-64 [PubMed] Related Publications
The histone demethylase LSD1 (KDM1A) demethylates mono- and di-methylated (Me2) lysine (K) 4 on histone H3. High LSD1 expression blocks differentiation and confers a poor prognosis in acute myeloid leukemia (AML). Here, treatment with the novel LSD1 antagonist SP2509 attenuated the binding of LSD1 with the corepressor CoREST, increased the permissive H3K4Me3 mark on the target gene promoters, and increased the levels of p21, p27 and CCAAT/enhancer binding protein α in cultured AML cells. In addition, SP2509 treatment or LSD1 shRNA inhibited the colony growth of AML cells. SP2509 also induced morphological features of differentiation in the cultured and primary AML blasts. SP2509 induced more apoptosis of AML cells expressing mutant NPM1 than mixed-lineage leukemia fusion oncoproteins. Treatment with SP2509 alone significantly improved the survival of immune-depleted mice following tail-vein infusion and engraftment of cultured or primary human AML cells. Co-treatment with pan-HDAC inhibitor (HDI) panobinostat (PS) and SP2509 was synergistically lethal against cultured and primary AML blasts. Compared with each agent alone, co-treatment with SP2509 and PS significantly improved the survival of the mice engrafted with the human AML cells, without exhibiting any toxicity. Collectively, these findings show that the combination of LSD1 antagonist and pan-HDI is a promising therapy warranting further testing against AML.

Fetahu IS, Höbaus J, Aggarwal A, et al.
Calcium-sensing receptor silencing in colorectal cancer is associated with promoter hypermethylation and loss of acetylation on histone 3.
Int J Cancer. 2014; 135(9):2014-23 [PubMed] Article available free on PMC after 15/12/2015 Related Publications
The calcium-sensing receptor (CaSR) is suggested to mediate the antiproliferative effects of calcium in colon. However, in colorectal cancer (CRC) the expression of the CaSR is silenced and the underlying mechanisms leading to its loss are poorly understood. We investigated whether loss of the CaSR expression in colorectal tumors is caused by DNA hypermethylation and imbalance of transcriptionally permissive/repressive histone alterations. We observed significantly lower CaSR mRNA expression (n = 65, p < 0.001) in colorectal tumors compared with the adjacent mucosa from the same patient. Immunofluorescence staining confirmed downregulation of the CaSR protein also. The CaSR promoter was methylated to a greater extent in tumors compared with adjacent mucosa as determined by bisulfite sequencing (n = 20, p < 0.01) and by pyrosequencing (n = 45, p < 0.001), and methylation correlated inversely with mRNA expression (n = 20, ρ = -0.310, p < 0.05 and n = 45, ρ = -0.588, p < 0.001). Treatments with 5-aza-2'-deoxycytidine (DAC), a DNA methyltransferase inhibitor and/or with two different histone deacetylase inhibitors, trichostatin A (TSA) or suberoylanilide hydroxamic acid (SAHA) restored the expression of CaSR in colon cancer cells. Restored CaSR expression in Coga1A and HT29 cells was functional. Inhibition of lysine-specific demethylase 1 (LSD1) to prevent demethylation of mono- and dimethylated H3K4, increased CaSR expression only marginally. Our data show that hypermethylation of the CaSR promoter and H3K9 deacetylation, but not H3K4me2 demethylation are important factors that cause silencing of the CaSR in colorectal cancer.

Miura S, Maesawa C, Shibazaki M, et al.
Immunohistochemistry for histone h3 lysine 9 methyltransferase and demethylase proteins in human melanomas.
Am J Dermatopathol. 2014; 36(3):211-6 [PubMed] Related Publications
Methylation and demethylation of histone H3 lysine 9 (H3K9) play a role in the transcriptional regulation of several cancer-related genes and are closely associated with malignant tumor behavior. A novel study has recently demonstrated that SETDB1, a member of the H3K9 methyltransferases, accelerates tumor formation significantly in a zebrafish melanoma model. However, the expression of H3K9 methyltransferases including SETDB1 and demethylases has not been systematically examined in samples of human melanoma. Here, we used immunohistochemistry to examine the expression of the H3K9 methyltransferases, EHMT2 and SETDB1, and a H3K9 demethylase, LSD1, in 67 patients with melanoma. Overexpression of EHMT2, SETDB1, and LSD1 was observed in 14 (21%), 38 (57%), and 53 (79%) of the 67 patients, respectively. A significant relationship was observed between overexpression of EHMT2 or SETDB1 and aggressive tumor behavior such as lymph node metastasis and/or distant metastasis (P < 0.05), whereas no significant relationship was evident for LSD1 immunoreactivity. Univariate log-rank tests demonstrated that patients with melanoma overexpressing EHMT2 had a poorer outcome (P < 0.001), whereas overexpression of SETDB1 or LSD1 had no prognostic impact. These results suggest that overexpression of EHMT2 might be a prognostic marker in patients with melanoma.

Qin Y, Zhu W, Xu W, et al.
LSD1 sustains pancreatic cancer growth via maintaining HIF1α-dependent glycolytic process.
Cancer Lett. 2014; 347(2):225-32 [PubMed] Related Publications
The histone demethylase LSD1 (lysine specific demethylase 1) plays an important role in the epigenetic regulation of gene transcription. Our study investigated the role of LSD1 in pancreatic cancer and demonstrated that LSD1 was significantly up-regulated in pancreatic cancer patient tissue samples, and elevated LSD1 protein levels positively correlated with overall survival of pancreatic cancer patients. Using in vitro and in vivo models, we demonstrated that knock-down of LSD1 repressed proliferation and tumorigenicity of pancreatic cancer cells. Mechanistically, our study demonstrated that LSD1 synergized with HIF1α (hypoxia inducible factor-1α) in maintaining glycolytic process, which fueled pancreatic cancer uncontrolled proliferation.

Sakane C, Okitsu T, Wada A, et al.
Inhibition of lysine-specific demethylase 1 by the acyclic diterpenoid geranylgeranoic acid and its derivatives.
Biochem Biophys Res Commun. 2014; 444(1):24-9 [PubMed] Related Publications
Lysine-specific demethylase 1 (LSD1) is upregulated in many cancers, especially neuroblastoma. We set out to explore whether geranylgeranoic acid (GGA) inhibits LSD1 activity by using recombinant human LSD1. GGA inhibited LSD1 activity with IC50 similar to that of the clinically used drug tranylcypromine. In human neuroblastoma SH-SY5Y cells, GGA induced NTRK2 gene expression alongside upregulation of histone H3 with dimethylated lysine-4 in the regulatory regions of the NTRK2 gene. Dihydrogenation of GGA reinforced the LSD1-inhibitory effect in a position-dependent manner. The inhibitory effects of dihydro-derivatives of GGA on recombinant LSD1 strongly correlated with the induction of NTRK2 gene expression in SH-SY5Y cells. These data demonstrate for the first time the efficient LSD1-inhibitor activity of GGA and its derivatives, providing a novel prospect of preventing cancer onset by using GGA to regulate epigenetic modification.

Ding D, Liu X, Guo SW
Overexpression of lysine-specific demethylase 1 in ovarian endometriomas and its inhibition reduces cellular proliferation, cell cycle progression, and invasiveness.
Fertil Steril. 2014; 101(3):740-9 [PubMed] Related Publications
OBJECTIVE: To investigate whether lysine-specific demethylase 1 (LSD1) is aberrantly expressed in endometriomas and whether treatment with tranylcypromine, an LSD1 inhibitor, has any effect on cell viability, cell cycle, and invasiveness.
DESIGN: Laboratory study using human tissues.
SETTING: Academic hospital.
PATIENT(S): Forty-two ectopic endometrial tissue samples, their homologue eutopic endometrial tissue samples, and 70 control endometrial tissue samples.
INTERVENTION(S): Immunohistochemistry analysis of LSD1 of all human tissue samples, and Western blot analysis, quantitative real-time reverse-transcription polymerase chain reaction analysis, cell viability assay, cell cycle analysis, and invasion assay of eutopic and ectopic endometriotic stromal cells and normal endometrial stromal cells.
MAIN OUTCOME MEASURE(S): Immunostaining levels of LSD1, gene and protein expression levels, cell viability, cell cycles, and invasiveness.
RESULT(S): The expression of the LSD1 gene and protein in endometriosis was elevated. Treatment of endometriotic stromal cells with tranylcypromine statistically significantly reduced the cellular proliferation, cell cycle progression, and invasiveness.
CONCLUSION(S): Because DNA and histones are intimately intertwined and work in concert in transcription regulation, conceivably histone demethylation activity of LSD1 could be wide ranging. The inhibition of LSD1 activity by tranylcypromine and the resultant inhibition of proliferation, cell cycle progression, and invasiveness suggest that LSD1 may be a candidate therapeutic target for endometriosis.

Yang H, Li Q, Zhao W, et al.
miR-329 suppresses the growth and motility of neuroblastoma by targeting KDM1A.
FEBS Lett. 2014; 588(1):192-7 [PubMed] Related Publications
MicroRNAs (miRNAs) act as key regulators of multiple cancers. miR-329 functions as a tumor suppressor in some malignancies. However, its role in neuroblastoma remains poorly understood. We found that miR-329 was decreased in metastatic tumor tissues compared with matched primary tumor tissues. Forced overexpression of miR-329 substantially suppressed cell proliferation, colony formation, migration, and invasion of neuroblastoma cells. Lysine-specific demethylase 1 (KDM1A) was found to be a target of miR-329. Furthermore, down-regulation of KDM1A by shRNA performed similar effects with overexpression of miR-329. Overexpression of KDM1A partially reversed the tumor suppressive effects of miR-329 in neuroblastoma cells. Collectively, miR-329 may suppress neuroblastoma cell growth and motility partially by targeting KDM1A.

Pajtler KW, Weingarten C, Thor T, et al.
The KDM1A histone demethylase is a promising new target for the epigenetic therapy of medulloblastoma.
Acta Neuropathol Commun. 2013; 1:19 [PubMed] Article available free on PMC after 15/12/2015 Related Publications
BACKGROUND: Medulloblastoma is a leading cause of childhood cancer-related deaths. Current aggressive treatments frequently lead to cognitive and neurological disabilities in survivors. Novel targeted therapies are required to improve outcome in high-risk medulloblastoma patients and quality of life of survivors. Targeting enzymes controlling epigenetic alterations is a promising approach recently bolstered by the identification of mutations in histone demethylating enzymes in medulloblastoma sequencing efforts. Hypomethylation of lysine 4 in histone 3 (H3K4) is also associated with a dismal prognosis for medulloblastoma patients. Functional characterization of important epigenetic key regulators is urgently needed.
RESULTS: We examined the role of the H3K4 modifying enzyme, KDM1A, in medulloblastoma, an enzyme also associated with malignant progression in the closely related tumor, neuroblastoma. Re-analysis of gene expression data and immunohistochemistry of tissue microarrays of human medulloblastomas showed strong KDM1A overexpression in the majority of tumors throughout all molecular subgroups. Interestingly, KDM1A knockdown in medulloblastoma cell lines not only induced apoptosis and suppressed proliferation, but also impaired migratory capacity. Further analyses revealed bone morphogenetic protein 2 (BMP2) as a major KDM1A target gene. BMP2 is known to be involved in development and differentiation of granule neuron precursor cells (GNCPs), one potential cell of origin for medulloblastoma. Treating medulloblastoma cells with the specific KDM1A inhibitor, NCL-1, significantly inhibited growth in vitro.
CONCLUSION: We provide the first evidence that a histone demethylase is functionally involved in the regulation of the malignant phenotype of medulloblastoma cells, and lay a foundation for future evaluation of KDM1A-inihibiting therapies in combating medulloblastoma.

Zheng YC, Duan YC, Ma JL, et al.
Triazole-dithiocarbamate based selective lysine specific demethylase 1 (LSD1) inactivators inhibit gastric cancer cell growth, invasion, and migration.
J Med Chem. 2013; 56(21):8543-60 [PubMed] Article available free on PMC after 15/12/2015 Related Publications
Lysine specific demethylase 1 (LSD1), the first identified histone demethylase, plays an important role in epigenetic regulation of gene activation and repression. The up-regulated LSD1's expression has been reported in several malignant tumors. In the current study, we designed and synthesized five series of 1,2,3-triazole-dithiocarbamate hybrids and screened their inhibitory activity toward LSD1. We found that some of these compounds, especially compound 26, exhibited the most specific and robust inhibition of LSD1. Interestingly, compound 26 also showed potent and selective cytotoxicity against LSD1 overexpressing gastric cancer cell lines MGC-803 and HGC-27, as well as marked inhibition of cell migration and invasion, compared to 2-PCPA. Furthermore, compound 26 effectively reduced the tumor growth bared by human gastric cancer cells in vivo with no signs of adverse side effects. These findings suggested that compound 26 deserves further investigation as a lead compound in the treatment of LSD1 overexpressing gastric cancer.

Lan W, Zhang D, Jiang J
The roles of LSD1-mediated epigenetic modifications in maintaining the pluripotency of bladder cancer stem cells.
Med Hypotheses. 2013; 81(5):823-5 [PubMed] Related Publications
Bladder cancer stem cells (BCSCs) may be the source for tumorigenesis, recurrence, and resistance to treatment of bladder carcinoma. Lysine-specific demethylase 1 (LSD1) plays crucial roles in the pluripotency maintenance of embryonic and cancer stem cells through the epigenetical modification of the associated genes, such as the regulation of bivalent domain at regulatory region of the developmental genes. It has also been found that LSD1 expression is elevated in clinical bladder cancer tissues compared with in normal tissues, and LSD1 knock down could significantly result in the suppression of bladder cancer cell line proliferation. Furthermore, results from our unpublished study showed that elevated levels of LSD1 are highly associated with the grades of the cancers, and more interestingly, LSD1 was mainly presented in the basal layer of bladder carcinoma tissue, co-localizing with BCSCs. Thus we hypothesized that LSD1 is mainly expressed in BCSCs in bladder cancer tissues, and LSD1-mediated epigenetic modification of the developmental genes may play important roles in maintaining pluripotency of BCSCs. LSD1 may become a reliable prognostic indicator and could serve as a molecular target in bladder cancer therapy.

Li X, Wu Z, Mei Q, et al.
Long non-coding RNA HOTAIR, a driver of malignancy, predicts negative prognosis and exhibits oncogenic activity in oesophageal squamous cell carcinoma.
Br J Cancer. 2013; 109(8):2266-78 [PubMed] Article available free on PMC after 15/12/2015 Related Publications
BACKGROUND: HOX transcript antisense RNA (HOTAIR), which is expressed from the homebox C gene (HOXC) locus, is capable of reprogramming chromatin organisation and promoting cancer cell metastasis and can simultaneously bind the polycomb repressive complex 2, which enhances H3K27 trimethylation, and the LSD1-CoREST-REST complex, which is critical for H3K4 demethylation. Clinically, the overexpression of HOTAIR is a powerful predictor of the tumour progression and overall survival in patients with diverse cancers. The relationship between HOTAIR and oesophageal squamous cell carcinoma (ESCC), however, remains unclear. We investigated the role of HOTAIR in the pathogenesis of ESCC.
METHODS: We used quantitative real-time PCR to determine the level of HOTAIR in ESCC cell lines and 100 ESCC samples from patients; 56 adjacent non-neoplastic tissues were used as controls. We measured the effect of HOTAIR knockdown and overexpression in ESCC cell lines using colony formation assays, anchorage-independent growth assays, the CCK-8 assay, transwell migration and invasion assays, and Annexin V-binding assays. We analysed the growth of ESCC xenograft tumours in nude mice. Changes in the gene expression and methylation levels in ESCC cell lines were analysed using gene expression microarrays and the Infinium HumanMethylation450K BeadChip assay, respectively. results: The levels of HOTAIR were increased in ESCC cell lines and patient samples compared with the controls; the expression levels correlated with the disease stage and survival time. The knockdown of HOTAIR in the KYSE510 and KYSE180 ESCC cell lines using small hairpin RNAs (shRNAs) reduced the ability of the cells to form foci, migrate, and invade the extracellular matrix in culture, altered cell cycle progression, and increased the sensitivity of the cells to apoptosis. The HOTAIR knockdown reduced cancer cell metastasis in vivo, and the tumours formed by HOTAIR-silenced ESCC cells were smaller, both in size and weight, than the tumours and metastases formed by the shRNA vector control cells in a mouse xenograft model. The results of the gene microarray study showed that HOTAIR reprogrammed the gene expression profile of ESCC cells, and the gene ontology analysis revealed an enrichment in genes that are important for tumorigenesis, such as genes involved in cell migration and the regulation of the cell cycle. Comparing the gene expression profiles and DNA methylation analysis between the KYSE180 and KYSE180_HOTAIR cells revealed that only a small proportion of the methylation changes were correlated with gene expression changes.
CONCLUSION: HOX transcript antisense RNA is upregulated in ESCC cell lines and patient samples, and promotes ESCC cell proliferation and tumour metastasis in mice. The knockdown of HOTAIR resulted in significant changes in gene expression, and data analysis suggested that HOTAIR-mediated gene regulation has a critical role in ESCC progression and is a novel epigenetic molecular target for treating ESCC patients.

Tang M, Shen H, Jin Y, et al.
The malignant brain tumor (MBT) domain protein SFMBT1 is an integral histone reader subunit of the LSD1 demethylase complex for chromatin association and epithelial-to-mesenchymal transition.
J Biol Chem. 2013; 288(38):27680-91 [PubMed] Article available free on PMC after 15/12/2015 Related Publications
Chromatin readers decipher the functional readouts of histone modifications by recruiting specific effector complexes for subsequent epigenetic reprogramming. The LSD1 (also known as KDM1A) histone demethylase complex modifies chromatin and represses transcription in part by catalyzing demethylation of dimethylated histone H3 lysine 4 (H3K4me2), a mark for active transcription. However, none of its currently known subunits recognizes methylated histones. The Snai1 family transcription factors are central drivers of epithelial-to-mesenchymal transition (EMT) by which epithelial cells acquire enhanced invasiveness. Snai1-mediated transcriptional repression of epithelial genes depends on its recruitment of the LSD1 complex and ensuing demethylation of H3K4me2 at its target genes. Through biochemical purification, we identified the MBT domain-containing protein SFMBT1 as a novel component of the LSD1 complex associated with Snai1. Unlike other mammalian MBT domain proteins characterized to date that selectively recognize mono- and dimethylated lysines, SFMBT1 binds di- and trimethyl H3K4, both of which are enriched at active promoters. We show that SFMBT1 is essential for Snai1-dependent recruitment of LSD1 to chromatin, demethylation of H3K4me2, transcriptional repression of epithelial markers, and induction of EMT by TGFβ. Carcinogenic metal nickel is a widespread environmental and occupational pollutant. Nickel alters gene expression and induces EMT. We demonstrate the nickel-initiated effects are dependent on LSD1-SFMBT1-mediated chromatin modification. Furthermore, in human cancer, expression of SFMBT1 is associated with mesenchymal markers and unfavorable prognosis. These results highlight a critical role of SFMBT1 in epigenetic regulation, EMT, and cancer.

Huang Z, Li S, Song W, et al.
Lysine-specific demethylase 1 (LSD1/KDM1A) contributes to colorectal tumorigenesis via activation of the Wnt/β-catenin pathway by down-regulating Dickkopf-1 (DKK1) [corrected].
PLoS One. 2013; 8(7):e70077 [PubMed] Article available free on PMC after 15/12/2015 Related Publications
We collected paired samples of tumor and adjacent normal colorectal tissues from 22 patients with colorectal carcinoma to compare the differences in the expression of lysine specific demethylase 1 (LSD1) in these two tissues. The results showed that in 19 paired samples (86.4%), LSD1 is more highly expressed in tumor tissue than in normal tissue. To explore the role of LSD1 in colorectal tumorigenesis, we used somatic cell gene targeting to generate an LSD1 knockout (KO) HCT 116 human colorectal cancer cell line as a research model. The analysis of phenotypic changes showed that LSD1 KO colorectal cancer cells are less tumorigenic, both in vivo and in vitro. The differential expression analysis of the cells by mRNA sequencing (RNA-Seq) yielded 2,663 differentially expressed genes, and 28 of these genes had highly significant differences (Q <0.01). We then selected the 4 colorectal cancer-related genes ADM, DKK1, HAS3 and SMURF2 for quantitative real-time PCR verification. The results showed that the differences in the expression of ADM, DKK1 and HAS3 were consistent with those measured using the RNA-Seq data. As DKK1 was the gene with the most significant differential expression, we analyzed the key proteins of the DKK1-related Wnt/β-catenin signaling pathway and found that, after knocking out LSD1, the amount of free β-catenin translocated to the nucleus was significantly reduced and that the transcription of the signaling pathway target gene c-Myc was down-regulated. Our studies show that LSD1 activates the Wnt/β-catenin signaling pathway by down-regulating the pathway antagonist DKK1, which may be one of the mechanisms leading to colorectal tumorigenesis.

Lin Y, Dong C, Zhou BP
Epigenetic regulation of EMT: the Snail story.
Curr Pharm Des. 2014; 20(11):1698-705 [PubMed] Article available free on PMC after 15/12/2015 Related Publications
While the epithelial-mesenchymal transition (EMT) plays a fundamental role during development, its deregulation can adversely promote tumor metastasis. The phenotypic and cellular plasticity of EMT indicates that it is subject to epigenetic regulation. A hallmark of EMT is E-cadherin suppression. In this review, we try to embrace recent findings on the transcription factor Snail-mediated epigenetic silencing of E-cadherin. Our studies as well as those of others independently demonstrated that Snail can recruit various epigenetic machineries to the E-cadherin promoter. Based on these results, we propose a model of epigenetic regulation of EMT governed by Snail. Briefly, recruitment of the LSD1/HDAC complex by Snail facilitates histone H3K4 demethylation and H3/H4 deacetylation. Histone deacetylation may promote subsequent recruitment of PRC2 to methylate H3K27, while H3K4 demethylation favors the association of H3K9 methyltransferases G9a and Suv39H1. Finally, DNA methyltransferases (DNMTs) can be recruited to the promoter area in a G9a/Suv39H1-dependent manner. Together, these chromatin-modifying enzymes function in a Snail-mediated, highly orchestrated fashion to suppress E-cadherin. Disruption of the connection between Snail and these epigenetic machineries may represent an efficient strategy for the treatment of EMT-related diseases, including tumor metastasis.

Yu Y, Wang B, Zhang K, et al.
High expression of lysine-specific demethylase 1 correlates with poor prognosis of patients with esophageal squamous cell carcinoma.
Biochem Biophys Res Commun. 2013; 437(2):192-8 [PubMed] Related Publications
Recent studies have elucidated the role of lysine-specific demethylase 1 (LSD1), a member of the histone demethylases, in epigenetic regulation of tumor suppressing/promoting genes and neoplastic growth. However, the expression of LSD1 in patients with esophageal squamous cell carcinoma (ESCC) is still unknown. Here, we reported that LSD1 expression was elevated in cancerous tissue and correlated with lymph node metastasis and poorer overall survival in patients with ESCC. Compared to EC109 cells, LSD1 expression was unregulated in aggressive cancer cell lines KYSE450 and KYSE150. Knockdown of LSD1 using lentivirus delivery of LSD1-specific shRNA abrogated the migration and invasion of ESCC cells in vitro. Further, a LSD1 inhibitor, tranylcypromine, suppressed H3K4me2 demethylation and attenuated cellular motility and invasiveness in a dose-dependent manner. Taken together, these data suggested that LSD1 was a potential prognostic maker and may be a molecular target for inhibiting invasion and metastasis in ESCC.

Katoh M
Functional and cancer genomics of ASXL family members.
Br J Cancer. 2013; 109(2):299-306 [PubMed] Article available free on PMC after 15/12/2015 Related Publications
Additional sex combs-like (ASXL)1, ASXL2 and ASXL3 are human homologues of the Drosophila Asx gene that are involved in the regulation or recruitment of the Polycomb-group repressor complex (PRC) and trithorax-group (trxG) activator complex. ASXL proteins consist of ASXN, ASXH, ASXM1, ASXM2 and PHD domains. ASXL1 directly interacts with BAP1, KDM1A (LSD1), NCOA1 and nuclear hormone receptors (NHRs), such as retinoic acid receptors, oestrogen receptor and androgen receptor. ASXL family members are epigenetic scaffolding proteins that assemble epigenetic regulators and transcription factors to specific genomic loci with histone modifications. ASXL1 is involved in transcriptional repression through an interaction with PRC2 and also contributes to transcriptional regulation through interactions with BAP1 and/or NHR complexes. Germ-line mutations of human ASXL1 and ASXL3 occur in Bohring-Opitz and related syndromes. Amplification and overexpression of ASXL1 occur in cervical cancer. Truncation mutations of ASXL1 occur in colorectal cancers with microsatellite instability (MSI), malignant myeloid diseases, chronic lymphocytic leukaemia, head and neck squamous cell carcinoma, and liver, prostate and breast cancers; those of ASXL2 occur in prostate cancer, pancreatic cancer and breast cancer and those of ASXL3 are observed in melanoma. EPC1-ASXL2 gene fusion occurs in adult T-cell leukaemia/lymphoma. The prognosis of myeloid malignancies with misregulating truncation mutations of ASXL1 is poor. ASXL family members are assumed to be tumour suppressive or oncogenic in a context-dependent manner.

Vicent GP, Nacht AS, Zaurin R, et al.
Unliganded progesterone receptor-mediated targeting of an RNA-containing repressive complex silences a subset of hormone-inducible genes.
Genes Dev. 2013; 27(10):1179-97 [PubMed] Article available free on PMC after 15/12/2015 Related Publications
A close chromatin conformation precludes gene expression in eukaryotic cells. Genes activated by external cues have to overcome this repressive state by locally changing chromatin structure to a more open state. Although much is known about hormonal gene activation, how basal repression of regulated genes is targeted to the correct sites throughout the genome is not well understood. Here we report that in breast cancer cells, the unliganded progesterone receptor (PR) binds genomic sites and targets a repressive complex containing HP1γ (heterochromatin protein 1γ), LSD1 (lysine-specific demethylase 1), HDAC1/2, CoREST (corepressor for REST [RE1 {neuronal repressor element 1} silencing transcription factor]), KDM5B, and the RNA SRA (steroid receptor RNA activator) to 20% of hormone-inducible genes, keeping these genes silenced prior to hormone treatment. The complex is anchored via binding of HP1γ to H3K9me3 (histone H3 tails trimethylated on Lys 9). SRA interacts with PR, HP1γ, and LSD1, and its depletion compromises the loading of the repressive complex to target chromatin-promoting aberrant gene derepression. Upon hormonal treatment, the HP1γ-LSD1 complex is displaced from these constitutively poorly expressed genes as a result of rapid phosphorylation of histone H3 at Ser 10 mediated by MSK1, which is recruited to the target sites by the activated PR. Displacement of the repressive complex enables the loading of coactivators needed for chromatin remodeling and activation of this set of genes, including genes involved in apoptosis and cell proliferation. These results highlight the importance of the unliganded PR in hormonal regulation of breast cancer cells.

Amente S, Lania L, Majello B
The histone LSD1 demethylase in stemness and cancer transcription programs.
Biochim Biophys Acta. 2013; 1829(10):981-6 [PubMed] Related Publications
DNA and histone chromatin modifying enzymes play a crucial role in chromatin remodeling in several biological processes. Lysine-specific demethylase 1 (LSD1), the first identified histone demethylase, is a relevant player in the regulation of a broad spectrum of biological processes including development, cellular differentiation, embryonic pluripotency and cancer. Here, we review recent insights on the role of LSD1 activity in chromatin regulatory complexes, its functional role in the epigenetic changes during embryonic development, in the establishment and maintenance of stemness and during cancer progression.

Aury-Landas J, Bougeard G, Castel H, et al.
Germline copy number variation of genes involved in chromatin remodelling in families suggestive of Li-Fraumeni syndrome with brain tumours.
Eur J Hum Genet. 2013; 21(12):1369-76 [PubMed] Article available free on PMC after 15/12/2015 Related Publications
Germline alterations of the tumour suppressor TP53 gene are detected approximately in 25% of the families suggestive of Li-Fraumeni syndrome (LFS), characterised by a genetic predisposition to a wide tumour spectrum, including soft-tissue sarcomas, osteosarcomas, premenopausal breast cancers, brain tumours, adrenocortical tumours, plexus choroid tumours, leukaemia and lung cancer. The aim of this study was to determine the contribution of germline copy number variations (CNVs) to LFS in families without detectable TP53 mutation. Using a custom-designed high-resolution array CGH, we evaluated the presence of rare germline CNVs in 64 patients fulfilling the Chompret criteria for LFS, but without any detectable TP53 alteration. In 15 unrelated patients, we detected 20 new CNVs absent in 600 controls. Remarkably, in four patients who had developed each brain tumour, the detected CNV overlap the KDM1A, MTA3, TRRAP or SIRT3 genes encoding p53 partners involved in histone methylation or acetylation. Focused analysis of SIRT3 showed that the CNV encompassing SIRT3 leads to SIRT3 overexpression, and that in vitro SIRT3 overexpression prevents apoptosis, increases G2/M and results in a hypermethylation of numerous genes. This study supports the causal role of germline alterations of genes involved in chromatin remodelling in genetic predisposition to cancer and, in particular, to brain tumours.

Rudolph T, Beuch S, Reuter G
Lysine-specific histone demethylase LSD1 and the dynamic control of chromatin.
Biol Chem. 2013; 394(8):1019-28 [PubMed] Related Publications
The flavin adenine dinucleotide-dependent amine oxidase LSD1 is the first molecularly defined histone demethylase, which specifically demethylates H3K4me1/me2. The enzyme dynamically controls a large variety of biological processes and is associated with protein complexes controlling transcriptional repression and activation. Molecular analysis of the Drosophila LSD1 homolog revealed new insights into the epigenetic control of heterochromatin formation during early embryogenesis, the establishment of transcriptional gene silencing and the epigenetic mechanisms associated with the maintenance of stem cell identity in primordial germline cells. This review summarizes our recent knowledge about the control of enzymatic activity and molecular function of LSD1 enzyme complexes in different model organisms including Schizosaccharomyces pombe, Drosophila and mammals. Finally, new developments in applied cancer research based on molecular analysis of LSD1 in cancer cells are discussed.

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