• biomarker
• cancer characteristics
• intronic polyadenylation
• pan-cancer

• Humans
• Neoplasms/genetics
• Neoplasms/metabolism
• Polyadenylation
• Introns
• Gene Expression Regulation, Neoplastic
• Prognosis
• Biomarkers, Tumor/genetics

• National Foundation for Cancer Research
• R01 CA272627 NIH HHS
• P30 CA012197 NCI NIH HHS
• Anderson Oncology Research Professorship
• R03 CA256100 NCI NIH HHS
• National Institutes of Health
• Comprehensive Cancer Center of Wake Forest Baptist Medical Center

• KDM3A
• biomarker
• colorectal cancer
• qRT-PCR

• BET
• BRD4
• Bromodomain and extraterminal domain inhibitors
• androgen receptor
• castration-resistant prostate cancer
• clinical trials
• epigenetics
• prostate cancer

• Myc protein
• RIOX2
• disease progression
• patient survival
• prostate cancer

• DDB2
• DNA damage
• H3K9me2
• JHDM2A
• arsenic

Castration-resistant prostate cancer (CRPC) with sustained androgen receptor (AR) signaling remains a critical clinical challenge, despite androgen depletion therapy. The Jumonji C-containing histone lysine demethylase family 4 (KDM4) members, KDM4A‒KDM4C, serve as critical coactivators of AR to promote tumor growth in prostate cancer and are candidate therapeutic targets to overcome AR mutations/alterations-mediated resistance in CRPC.

In this study, using a structure-based approach, we identified a natural product, myricetin, able to block the demethylation of histone 3 lysine 9 trimethylation by KDM4 members and evaluated its effects on CRPC. A structure-based screening was employed to search for a natural product that inhibited KDM4B. Inhibition kinetics of myricetin was determined. The cytotoxic effect of myricetin on various prostate cancer cells was evaluated. The combined effect of myricetin with enzalutamide, a second-generation AR inhibitor toward C4-2B, a CRPC cell line, was assessed. To improve bioavailability, myricetin encapsulated by poly lactic-co-glycolic acid (PLGA), the US food and drug administration (FDA)-approved material as drug carriers, was synthesized and its antitumor activity alone or with enzalutamide was evaluated using in vivo C4-2B xenografts.

Myricetin was identified as a potent α-ketoglutarate-type inhibitor that blocks the demethylation activity by KDM4s and significantly reduced the proliferation of both androgen-dependent (LNCaP) and androgen-independent CRPC (CWR22Rv1 and C4-2B). A synergistic cytotoxic effect toward C4-2B was detected for the combination of myricetin and enzalutamide. PLGA-myricetin, enzalutamide, and the combined treatment showed significantly greater antitumor activity than that of the control group in the C4-2B xenograft model. Tumor growth was significantly lower for the combination treatment than for enzalutamide or myricetin treatment alone.

These results suggest that myricetin is a pan-KDM4 inhibitor and exhibited potent cell cytotoxicity toward CRPC cells. Importantly, the combination of PLGA-encapsulated myricetin with enzalutamide is potentially effective for CRPC.

The online version contains supplementary material available at 10.1186/s12929-022-00812-3.

Numerous studies on the prognostic significance of lysine-specific demethylase 1 (LSD1) up-regulation in tumors have different outcomes. The inconsistency originated from various studies looking into the association between LSD1 and tumor cells has prompted the decision of this quantitative systematic review to decipher how up-regulated LSD1 and overall survival (OS) or recurrence-free survival (RFS) or disease-free survival (DFS) are linked in tumor patients.

Articles were searched from online databases such as Embase, Web of Science Core, PubMed, Google Scholar, and Scopus. The extraction of the hazard ratios (HR) with their 95% confidence intervals (CIs) was attained and survival data of 3151 tumor patients from 17 pieces of related research were used for this meta-analysis.

To shed light on the link between LSD1 up-regulation and the prognosis of diverse tumors, the pooled hazard ratios (HRs) with their 95% confidence intervals (CIs) were determined. In this meta-analysis, it was observed that LSD1 up-regulation is linked with poor OS (HR = 2.08, 95% CI: 1.66–2.61, P < .01) and RFS (HR = 3.09, 95% CI: 1.81–5.26, P < .01) in tumor patients. However, LSD1 up-regulation was not linked to DFS (HR = 1.49, 95% CI: .83–2.69, P = .18) in tumor patients. The subcategory examination grouped by tumor type and ethnicity showed that LSD1 up-regulation was linked with a poor outcome in the esophageal tumor and hepatocellular carcinoma and Asian patients, respectively. For clinical-pathological factors, up-regulated LSD1 was significantly linked with Lymph node status.

Despite the shortfall of the present work, this meta-analysis proposes that LSD1 up-regulation may be a prognostic biomarker for patients with tumors including esophageal tumors and hepatocellular carcinoma. We propose that large-scale studies are vital to substantiate these outcomes.

• cancer patients
• esophageal tumor
• meta-analysis
• overall survival
• up-regulated lysine-specific demethylase 1

• KDM4
• KDM4 inhibitor
• anticancer agent
• epigenetic agent
• histone H3K9 demethylase

Our three-dimensional organotypic culture revealed that human histone demethylase (KDM) 4C, a histone lysine demethylase, hindered the acini morphogenesis of RWPE-1 prostate cells, suggesting its potential oncogenic role. Knockdown (KD) of KDM4C suppressed cell proliferation, soft agar colony formation, and androgen receptor (AR) transcriptional activity in PCa cells as well as reduced tumor growth of human PCa cells in zebrafish xenotransplantation assay. Micro-Western array (MWA) analysis indicated that KD of KDM4C protein decreased the phosphorylation of AKT, c-Myc, AR, mTOR, PDK1, phospho-PDK1 S241, KDM8, and proteins involved in cell cycle regulators, while it increased the expression of PTEN. Fluorescent microscopy revealed that KDM4C co-localized with AR and c-Myc in the nuclei of PCa cells. Overexpression of either AKT or c-Myc rescued the suppressive effect of KDM4C KD on PCa cell proliferation. Echoing the above findings, the mRNA and protein expression of KDM4C was higher in human prostate tumor tissues as compared to adjacent normal prostate tissues, and higher KDM4C protein expression in prostate tumors correlated to higher protein expression level of AKT and c-Myc. In conclusion, KDM4C promotes the proliferation of PCa cells via activation of c-Myc and AKT.

• AKT
• KDM4C
• Micro-Western Array
• c-Myc
• prostate cancer

Our previous work demonstrated that lncRNA-MALAT1 was overexpressed in recurrent colorectal cancer (CRC) and metastatic sites in post-surgical patients. However, the upstream regulatory mechanism of MALAT1 is not well-defined. Histone demethylase JMJD2C holds great potential of epigenetic regulating mechanism in tumor diseases, especially the moderating effect on the promoter activity of targeted genes associated closely with tumor development. Therefore, we herein investigated whether JMJD2C could epigeneticly regulate the promoter activity of MALAT1 and the downstream β-catenin signaling pathway, thereby affecting the metastatic abilities of CRC cells.

JMJD2C expressions in human CRC samples were detected by real-time PCR and immunohistochemistry staining. Gene silencing and overexpressing efficiencies of JMJD2C were confirmed by real-time PCR and western blot. The migration of CRC cells in vitro were tested by transwell and wound healing assays. The protein expression and cellular localization of JMJD2C and β-catenin were characterized by immunofluorescence staining and western blot. The histone methylation level of MALAT1 promoter region (H3K9me3 and H3K36me3) was tested by ChIP-PCR assays. The promoter activity of MALAT1 was detected by luciferase reporter assay. The expressions of MALAT1 and the downstream β-catenin signaling pathway related genes in CRC cells were detected by real-time PCR and western blot, respectively. The nude mice tail vein metastasis model was established to observe the effect of JMJD2C on the lung metastasis of CRC cells in vivo.

Our present results indicated that histone demethylase JMJD2C was overexpressed in matched CRC tumor tissues of primary and metastatic foci, and CRC patients with lower JMJD2C expression in primary tumors had better prognosis with longer OS (Overall Survival). The following biological function observation suggested that JMJD2C promoted CRC metastasis in vitro and in vivo. Further molecular mechanism investigation demonstrated that JMJD2C protein translocated into the nuclear, lowered the histone methylation level of MALAT1 promoter in the sites of H3K9me3 and H3K36me3, up-regulated the expression of MALAT1, and enhanced the β-catenin signaling pathway in CRC cells.

Our data demonstrated that JMJD2C could enhance the metastatic abilities of CRC cells in vitro and in vivo by regulating the histone methylation level of MALAT1 promoter, thereby up-regulating the expression of MALAT1 and enhancing the activity of β-catenin signaling pathway, providing that JMJD2C might be a novel therapeutic target for CRC metastasis.

• Colorectal cancer
• Histone demethylase JMJD2C
• MALAT1
• Metastasis
• β-Catenin signaling pathway

• DNMT
• HDAC
• PTM.
• TET
• epigenetic
• metalloenzymes.

Gastric cancer (GC) is a common malignant tumor of the digestive system. In addition, GC metastasis is an extremely complicated process. A previous study has found that lysine-specific demethylase 1 (LSD1) is abnormal expression in a variety of cancers and its overexpression correlates with aggressive disease and poor outcome.

qRT-PCR and Western blot assays were used to assess the expression of LSD1 in GC tissue samples and cell lines. Colony formation assay, CCK-8 assay, scratch-wound assay and transwell invasion, were performed to determine the effect of LSD1 on cell proliferation and migration as well as invasion in GC.

Our results show that LSD1 was up-regulated in GC tumor tissues and cell lines, and high expression level of LSD1 was found to be positively correlated with tumor size, lymph node metastasis and pathological grade. Moreover, LSD1 promoted cell proliferation, migration and invasion of GC. In addition, LSD1 regulated E-cadherin expression through demethylating H3K4me2, thereby promoting EMT in GC.

Our work indicated that LSD1 may be used as a potential target of gastric cancer.

• E-cadherin
• EMT
• H3K4me2
• LSD1
• gastric cancer

Malignant ovarian tumors bear the highest mortality rate among all gynecological cancers. Both late tumor diagnosis and tolerance to available chemical therapy increase patient mortality. Therefore, it is both urgent and important to identify biomarkers facilitating early identification and novel agents preventing recurrence. Accumulating evidence demonstrates that epigenetic aberrations (particularly histone modifications) are crucial in tumor initiation and development. Histone acetylation and methylation are respectively regulated by acetyltransferases-deacetylases and methyltransferases-demethylases, both of which are implicated in ovarian cancer pathogenesis. In this review, we summarize the most recent discoveries pertaining to ovarian cancer development arising from the imbalance of histone acetylation and methylation, and provide insight into novel therapeutic interventions for the treatment of ovarian carcinoma.

• Epigenetics
• Histone acetylation
• Histone methylaiton
• Ovarian cancer

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.

• Acute myeloid leukemia
• Carcinogenesis
• Histone demethylation
• KDM1A
• TLL

• KDM3A
• breast cancer
• metastasis
• prognosis

• Wnt signaling
• cancer biology
• colorectal cancer
• histone demethylase
• transcriptional coactivator

The lysine demethylase 3A (KDM3A, JMJD1A or JHDM2A) controls transcriptional networks in a variety of biological processes such as spermatogenesis, metabolism, stem cell activity, and tumor progression. We matched transcriptomic and ChIP-Seq profiles to decipher a genome-wide regulatory network of epigenetic control by KDM3A in prostate cancer cells. ChIP-Seq experiments monitoring histone 3 lysine 9 (H3K9) methylation marks show global histone demethylation effects of KDM3A. Combined assessment of histone demethylation events and gene expression changes presented major transcriptional activation suggesting that distinct oncogenic regulators may synergize with the epigenetic patterns by KDM3A. Pathway enrichment analysis of cells with KDM3A knockdown prioritized androgen signaling indicating that KDM3A plays a key role in regulating androgen receptor activity. Matched ChIP-Seq and knockdown experiments of KDM3A in combination with ChIP-Seq of the androgen receptor resulted in a gain of H3K9 methylation marks around androgen receptor binding sites of selected transcriptional targets in androgen signaling including positive regulation of KRT19, NKX3-1, KLK3, NDRG1, MAF, CREB3L4, MYC, INPP4B, PTK2B, MAPK1, MAP2K1, IGF1, E2F1, HSP90AA1, HIF1A, and ACSL3. The cancer systems biology analysis of KDM3A-dependent genes identifies an epigenetic and transcriptional network in androgen response, hypoxia, glycolysis, and lipid metabolism. Genome-wide ChIP-Seq data highlights specific gene targets and the ability of epigenetic master regulators to control oncogenic pathways and cancer progression.

• ChIP-Seq
• cancer systems biology
• epigenomics
• oncogene
• prostate cancer

Jumonji domain-containing protein 1A (JMJD1A) plays a key role in the development and progression of several cancers. Here, we showed that the expression of JMJD1A is increased in cervical cancer cells and tissues, and that suppression of JMJD1A inhibits proliferation, migration, and invasion of cervical cancer cells. JMJD1A induced transcription of c-Myc, which is essential for cervical cancer growth and progression. Clinical data showed that JMJD1A expression correlated with lymph node metastasis (P=0.031) and FIGO stage (P=0.007). Increased c-Myc levels were associated with tumor differentiation (P=0.007) and FIGO stage (P<0.001). JMJD1A protein levels correlated with c-Myc expression (P<0.001), and high co-expression of the two proteins correlated with a poor prognosis. Survival analysis showed that JMJD1A and c-Myc levels are independent prognostic factors for cervical cancer patients. These results suggest that JMJD1A is a promising therapeutic target in cervical cancer.

• JMJD1A
• c-Myc
• cervical cancer
• immunohistochemistry
• prognosis

Histone methylation is one of the major epigenetic modifications, and various histone methylases and demethylases participate in the epigenetic regulating. JMJD2C has been recently identified as one of the histone lysine demethylases. As one member of the Jumonji-C histone demethylase family, JMJD2C has the ability to demethylate tri- or di-methylated histone 3 and 2 in either K9 (lysine residue 9) or K36 (lysine residue 36) sites by an oxidative reaction, thereby affecting heterochromatin formation, genomic imprinting, X-chromosome inactivation, and transcriptional regulation of genes. JMJD2C was firstly found to involve in embryonic development and stem cell regulation. Afterwards, aberrant status of JMJD2C histone methylation was observed during the formation and development of various tumors, and it has been reported to play crucial roles in the progression of breast cancer, prostate carcinomas, osteosarcoma, blood neoplasms and so on, indicating that JMJD2C represents a promising anti-cancer target. In this review, we will focus on the research progress and prospect of JMJD2C in tumors, and provide abundant evidence for the functional application and therapeutic potential of targeting JMJD2C in tumors.

• JMJD2C
• epigenetic regulation
• histone demethylase
• tumor

Widespread prostate-specific antigen (PSA) testing notably increased the number of prostate cancer (PCa) diagnoses. However, about 30% of these patients have low-risk tumors that are not lethal and remain asymptomatic during their lifetime. Overtreatment of such patients may reduce quality of life and increase healthcare costs. Active surveillance (AS) has become an accepted alternative to immediate treatment in selected men with low-risk PCa. Despite much progress in recent years toward identifying the best candidates for AS in recent years, the greatest risk remains the possibility of misclassification of the cancer or missing a high-risk cancer. This is particularly worrisome in men with a life expectancy of greater than 10–15 years. The Prostate Cancer Research International Active Surveillance (PRIAS) study showed that, in addition to age and PSA at diagnosis, both PSA density (PSA-D) and the number of positive cores at diagnosis (two compared with one) are the strongest predictors for reclassification biopsy or switching to deferred treatment. However, there is still no consensus upon guidelines for placing patients on AS. Each institution has its own protocol for AS that is based on PRIAS criteria. Many different variables have been proposed as tools to enrol patients in AS: PSA-D, the percentage of freePSA, and the extent of cancer on biopsy (number of positive cores or percentage of core involvement). More recently, the Prostate Health Index (PHI), the 4 Kallikrein (4K) score, and other patient factors, such as age, race, and family history, have been investigated as tools able to predict clinically significant PCa. Recently, some reports suggested that epigenetic mapping differs significantly between cancer patients and healthy subjects. These findings indicated as future prospect the use of epigenetic markers to identify PCa patients with low-grade disease, who are likely candidates for AS. This review explores literature data about the potential of epigenetic markers as predictors of clinically significant disease.

• active surveillance
• epigenetic biomarkers
• prostate cancer

Toll-like receptor 4 (TLR4) is a pattern recognition receptors, a member of the Toll-like receptor family and it serves a role in innate and acquired immunity. It has previously been reported that TLR4 was overexpressed in a variety of tumor tissues and cells, including colorectal cancer, gastric cancer and ovarian cancer. In the tumor microenvironment, the TLR4 signaling pathway may be activated in order to upregulate forkhead box P3 (Foxp3) expression in regulatory T cells (Tregs), and thus enhance the immunosuppressive function of Tregs. Also, inflammatory cytokine release would be increased, which promotes tumor immune system evasion. Additionally, it has previously been reported that TLR4 activation may induce histone methylation changes at multiple sites. However, the effects of the alterations to histone methylation in the process of TLR4-associated tumor immune system evasion are not currently known. Histone methylation serves a critical role in regulating gene expression. Abnormal histone methylation is closely associated with tumor development and progression. In order to investigate the epigenetic mechanisms underlying Foxp3 regulation by TLR4, the human lung adenocarcinoma cell line A549 was used. In the present study, it was revealed that the expression level of H3K9me1/2 histone lysine demethylase 3A (KDM3A) was significantly increased following TLR 4 activation in the lung adenocarcinoma A549 cell line, whereas silencing of KDM3A expression led to significantly reduced Foxp3 expression under TLR4 regulation. This result suggests that KDM3A participates in TLR4 regulation of Foxp3 transcription. Additional analysis revealed that during nuclear transport of Foxp3, KDM3A may directly bind to the Foxp3 promoter and activate its transcription. This results in increased secretion of Foxp3-downstream inhibitory cytokines, including transforming growth factor-β1 (TGF-β1), interleukin 35 (IL-35) and heme oxygenase 1 (HO-1), which have immunosuppressive effects and ultimately facilitate the immune escape of lung cancer cells. From the results, the present study concluded that TLR4 activation promoted the expression of H3K9me1/2 demethylase KDM3A. KDM3A bound directly to the Foxp3 promoter and promoted Foxp3 transcription, thereby inducing the secretion of Foxp3-associated downstream inhibitory cytokines (TGF-β1, IL-35, and HO-1), ultimately facilitating the immune system evasion of lung adenocarcinoma.

• Toll-like receptor 4
• forkhead box p3
• inhibitory cytokines
• lung adenocarcinoma
• lysine demethylase 3A

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.

• DNMTi
• Histone modulators
• Prostate cancer

• Autophagy
• Beclin 1
• Glioma cells
• KDM4A
• LC3B-II/LC3B-I

• Cisplatin
• Gastric cancer
• LSD1
• Lentivirus
• shRNA

• EZH2
• Feedback
• JMJD1A
• Let-7c
• NSCLC
• Tumorigenesis

• Cancer
• Epigenetic regulator
• Jumonji histone demethylases
• p53

• KDM2A
• breast cancer
• copy number alteration
• gene amplification
• histone lysine demethylase

• Epigenetic
• KDM1A
• KDM1B
• LSD1
• LSD2

• Animals
• Cell Differentiation
• Enzyme Inhibitors/chemistry
• Hematopoietic Stem Cells/enzymology
• Hematopoietic Stem Cells/pathology
• Histone Demethylases/antagonists & inhibitors
• Histone Demethylases/chemistry
• Histone Demethylases/classification
• Histone Demethylases/metabolism
• Humans
• Neoplasms/enzymology
• Neoplasms/pathology
• Neural Stem Cells/enzymology
• Neural Stem Cells/pathology
• Protein Processing, Post-Translational

• T32-GM 8487-19 NIGMS NIH HHS
• T32-GM 7105-39 NIGMS NIH HHS
• T32 GM008487 NIGMS NIH HHS
• R01-GM65539 NIGMS NIH HHS
• T32 GM007105 NIGMS NIH HHS
• R01 GM065539 NIGMS NIH HHS

Lysine-specific demethylase 1(LSD1) is implicated in the tumorigenesis and progression in various cancers. However, the expression of LSD1 in epithelial ovarian cancer and its clinical significance has not been examined in detail.

Immunohistochemical was used to detect the expression of LSD1 in normal ovarian epithelial tissues, cystadenoma, borderline cystadenoma, and cystadenocarcinoma. Next, the correlations between expression of LSD1 and clinicopathological features was assessed in 96 species of serous cystadenocarcinoma and 36 species of mucinous cystadenocarcinoma.

Immunohistochemical results showed that the expression of LSD1 was gradually increased from benign cystadenoma and borderline cystadenoma to cystadenocarcinoma. The positive ratio of LSD1 expression was 50% in normal ovarian epithelial tissues, 72% in serous cystadenoma, 73% in mucinous cystadenoma, 82% in borderline serous cystadenoma, 83% in borderline mucinous cystadenoma, 94% in serous cystadenocarcinoma and 92% in mucinous cystadenocarcinoma, respectively. LSD1 expression levels were associated with International Federation of Gynecology and Obstetrics stage and lymphatic metastasis in both serous and mucinous cystadenocarcinoma samples. Kaplan-Meier curves suggested that overall survival time of patients with high LSD1 expression was significantly shorter than that of patients with low LSD1 expression. Multivariate Cox proportional hazard regression indicated that higher LSD1 expression was a significant independent predictor of poor survival of EOC patients (P = 0.016).

These results suggest that LSD1 may be involved in carcinogenesis and progression with promising therapeutic potential for epithelial ovarian cancer.

• esophageal squamous cell carcinoma
• gene prognostic signature
• histone demethylase
• histopathology

• Adult
• Aged
• Biomarkers, Tumor/analysis
• Carcinoma, Squamous Cell/genetics
• Carcinoma, Squamous Cell/mortality
• Carcinoma, Squamous Cell/pathology
• Esophageal Neoplasms/genetics
• Esophageal Neoplasms/mortality
• Esophageal Neoplasms/pathology
• Esophageal Squamous Cell Carcinoma
• Female
• Humans
• Jumonji Domain-Containing Histone Demethylases/genetics
• Kruppel-Like Factor 4
• Male
• Middle Aged
• Predictive Value of Tests
• Prognosis
• Proportional Hazards Models

Inhibition of histone demethylases has within recent years advanced into a new strategy for treating cancer and other diseases. Targeting specific histone demethylases can be challenging, as the active sites of KDM1A-B and KDM4A-D histone demethylases are highly conserved. Most inhibitors developed up-to-date target either the cofactor- or substrate-binding sites of these enzymes, resulting in a lack of selectivity and off-target effects. This study describes the discovery of the first peptide-based inhibitors of KDM4 histone demethylases that do not share the histone peptide sequence or inhibit through substrate competition. Through screening of DNA-encoded peptide libraries against KDM1 and -4 histone demethylases by phage display, two cyclic peptides targeting the histone demethylase KDM4C were identified and developed as inhibitors by amino acid replacement, truncation, and chemical modifications. Hydrogen/deuterium exchange mass spectrometry revealed that the peptide-based inhibitors target KDM4C through substrate-independent interactions located on the surface remote from the active site within less conserved regions of KDM4C. The sites discovered in this study provide a new approach of targeting KDM4C through substrate- and cofactor-independent interactions and may be further explored to develop potent selective inhibitors and biological probes for the KDM4 family.

• chromatin modification
• epigenetic
• histone demethylation
• jumonji
• lysine methylation
• oxygenases

• Cytosine/metabolism
• DNA Methylation
• Epigenesis, Genetic
• Humans
• Inflammation/genetics
• Jumonji Domain-Containing Histone Demethylases/metabolism
• Metabolic Diseases/genetics
• Models, Molecular
• Multigene Family
• Neoplasms/genetics
• Neoplasms/metabolism
• Oxygenases/chemistry
• Oxygenases/physiology
• Phylogeny
• Polycomb Repressive Complex 2/metabolism
• Protein Conformation
• Protein Folding

• Wellcome Trust
• 092809 Wellcome Trust
• 20522 Versus Arthritis

Lysine-specific demethylase 1 (Lsd1/Aof2/Kdm1a), the first enzyme with specific lysine demethylase activity to be described, demethylates histone and non-histone proteins and is essential for mouse embryogenesis. Lsd1 interacts with numerous proteins through several different domains, most notably the tower domain, an extended helical structure that protrudes from the core of the protein. While there is evidence that Lsd1-interacting proteins regulate the activity and specificity of Lsd1, the significance and roles of such interactions in developmental processes remain largely unknown. Here we describe a hypomorphic Lsd1 allele that contains two point mutations in the tower domain, resulting in a protein with reduced interaction with known binding partners and decreased enzymatic activity. Mice homozygous for this allele die perinatally due to heart defects, with the majority of animals suffering from ventricular septal defects. Molecular analyses revealed hyperphosphorylation of E-cadherin in the hearts of mutant animals. These results identify a previously unknown role for Lsd1 in heart development, perhaps partly through the control of E-cadherin phosphorylation.

• Alleles
• Animals
• Cadherins/metabolism
• Disease Models, Animal
• Enzyme Activation
• Female
• Gene Expression Profiling
• Gene Expression Regulation, Developmental
• Heart Defects, Congenital/genetics
• Heart Defects, Congenital/metabolism
• Heart Defects, Congenital/pathology
• Heart Septal Defects, Ventricular/genetics
• Heart Septal Defects, Ventricular/metabolism
• Heart Septal Defects, Ventricular/pathology
• Histone Demethylases
• Homozygote
• Mice
• Mice, Knockout
• Oxidoreductases, N-Demethylating/genetics
• Oxidoreductases, N-Demethylating/metabolism
• Phosphorylation
• Point Mutation
• Pregnancy
• Protein Binding

• GASC1
• Histone demethylase
• esophageal squamous cell carcinoma
• immunohistochemistry
• lymph node metastasis

AIM: To investigate the clinicopathological features and prognostic value of lysine specific demethylase 1 (LSD1) in hepatocellular carcinoma (HCC).

METHODS: We examined LSD1 expression in 60 paired liver cancer tissues and adjacent noncancerous tissues by quantitative real time polymerase chain reaction (qRT-PCR) and Western blotting. In addition, we analyzed LSD1 expression in 198 HCC samples by immunohistochemistry. The relationship between LSD1 expression, clinicopathological features and patient survival was investigated.

RESULTS: Immunohistochemistry, Western blotting, and qRT-PCR consistently confirmed LSD1 overexpression in HCC tissues compared to adjacent non-neoplastic tissues (P < 0.01). Additionally, immunostaining showed more LSD1-positive cells in the higher tumor stage (T3-4) and tumor grade (G3) than in the lower tumor stage (T1-2, P < 0.001) and tumor grade (G1-2, P < 0.001), respectively. Moreover, HCC patients with high LSD1 expression had significantly lower 5-year overall survival rates (P < 0.001) and lower 5-year disease-free survival rates (P < 0.001), respectively. A Cox proportional hazards model further demonstrated that LSD1 over-expression was an independent predictor of poor prognosis for both 5-year disease-free survival [hazards ratio (HR) = 1.426, 95%CI: 0.672-2.146, P < 0.001] and 5-year overall survival (HR = 2.456, 95%CI: 1.234-3.932, P < 0.001) in HCC.

CONCLUSION: Our data suggest for the first time that the overexpression of LSD1 protein in HCC tissues indicates tumor progression and predicts poor prognosis.

• Hepatocellular carcinoma
• Lysine specific demethylase 1
• Tumor progression
• Prognosis

• Adult
• Aged
• Biomarkers, Tumor/genetics
• Carcinoma, Non-Small-Cell Lung/genetics
• Carcinoma, Non-Small-Cell Lung/metabolism
• Carcinoma, Non-Small-Cell Lung/mortality
• Carcinoma, Non-Small-Cell Lung/pathology
• Cell Line, Tumor
• Cell Movement/drug effects
• Cell Movement/genetics
• Cell Proliferation/drug effects
• Epithelial-Mesenchymal Transition/genetics
• Female
• Gene Expression Regulation, Neoplastic
• Histone Demethylases/antagonists & inhibitors
• Histone Demethylases/genetics
• Humans
• Immunohistochemistry
• Lung/drug effects
• Lung/metabolism
• Lung/pathology
• Lung Neoplasms/genetics
• Lung Neoplasms/metabolism
• Lung Neoplasms/pathology
• Male
• Middle Aged
• Neoplasm Invasiveness
• Pargyline/pharmacology
• Prognosis
• RNA, Small Interfering/genetics
• Survival Rate

• Animals
• Breast Neoplasms/metabolism
• Female
• Gene Expression Regulation, Neoplastic
• Histone Demethylases/antagonists & inhibitors
• Histone Demethylases/metabolism
• Histone-Lysine N-Methyltransferase/metabolism
• Histones/metabolism
• Humans
• Male
• Methylation
• Prostatic Neoplasms/metabolism
• Receptors, Steroid/metabolism