Lysine specific demethylase

Tissue development, homeostasis, and repair all require efficient progenitor expansion. Lysine-specific demethylase 1 (Lsd1) maintains plastic epigenetic states to promote progenitor proliferation while overexpressed Lsd1 protein causes oncogenic gene expression in cancer cells. However, the precise regulation of Lsd1 protein expression at the molecular level to drive progenitor differentiation remains unclear. Here, using Drosophila melanogaster oogenesis as our experimental system, we discovered molecular machineries that modify Lsd1 protein stability in vivo ...

Postnatal development of the gastrointestinal tract involves the establishment of the commensal microbiota, the acquisition of immune tolerance via a balanced immune cell composition, and maturation of the intestinal epithelium. While studies have uncovered an interplay between the first two, less is known about the role of the maturing epithelium. Here we show that intestinal-epithelial intrinsic expression of lysine-specific demethylase 1A (LSD1) is necessary for the postnatal maturation of intestinal epithelium and maintenance of this developed state during adulthood...

In this series we report the structure-based design, synthesis and anticancer activity evaluation of a series of eighteen cyclopropylamine containing cyanopyrimidine derivatives. The computational predictions of ADMET properties revealed appropriate aqueous solubility, high GI absorption, no BBB permeability, no Lipinski rule violations, medium total clearance and no mutagenic, tumorigenic, irritant and reproductive toxic risks for most of the compounds. Compounds VIIb, VIIi and VIIm emerged as the most potent anticancer agents among all compounds evaluated against 60 cancer cell lines through the one-dose (10 µM) sulforhodamine B assay...

The methylation and demethylation of lysine and arginine side chains are fundamental processes in gene regulation and disease development. Histone lysine methylation, controlled by histone lysine methyltransferases (KMTs) and histone lysine demethylases (KDMs), plays a vital role in maintaining cellular homeostasis and has been implicated in diseases such as cancer and aging. This study focuses on two members of the lysine demethylase (KDM) family, KDM4E and KDM6B, which are significant in gene regulation and disease pathogenesis...

INTRODUCTION: Lysine-specific demethylase 1 (LSD1) is emerging as a critical mediator of tumor progression in metastatic castration-resistant prostate cancer (mCRPC). Neuroendocrine prostate cancer (NEPC) is increasingly recognized as an adaptive mechanism of resistance in mCRPC patients failing androgen receptor axis-targeted therapies. Safe and effective LSD1 inhibitors are necessary to determine antitumor response in prostate cancer models. For this reason, we characterize the LSD1 inhibitor bomedemstat to assess its clinical potential in NEPC as well as other mCRPC pathological subtypes...

BACKGROUND: The incidence of thyroid cancer in women is 3-4-fold higher than in men. To characterize sex-specific molecular alterations in thyroid cancer, we examined the expression of sex-biased genes in normal thyroids and thyroid tumors. METHODS: Ingenuity pathways analysis was used to define sex-biased gene networks using data from the Cancer Genome Atlas (TCGA). Confirmatory studies were performed through the analysis of histone lysine demethylases (KDMs) expression by real-time PCR and immunostaining...

Previous studies have shown that ferroptosis of vascular smooth muscle cells (VSMCs) is involved in the development of aortic dissection (AD) and that histone methylation regulates this process. SP2509 acts as a specific inhibitor of lysine-specific demethylase 1 (LSD1), which governs a variety of biological processes. However, the effect of SP2509 on VSMC ferroptosis and AD remains to be elucidated. This aim of this study was to investigate the role and underlying mechanism of SP2509-mediated histone methylation on VSMC ferroptosis...

Baicalein has been implicated in the chemotherapy overcoming triple-negative breast cancer (TNBC). However, many unanswered questions remain regarding its role in treating TNBC. Here, we sought to demonstrate the molecular pathway mediated by baicalein in TNBC. Lysine-specific demethylase 4E (KDM4E), reduced in TNBC cells, was identified as a target protein of baicalein, and baicalein enhanced the protein expression and stability of KDM4E in TNBC cells. Knockdown of KDM4E attenuated the inhibitory effect of baicalein on TNBC cell activity, as demonstrated by intensified mobility, viability, and apoptosis resistance in TNBC cells...

Since the discovery of copper induces cell death(cuprotosis) in 2022, it has been one of the biggest research hotspots. cuprotosis related genes (CRGs) has been demonstrated to be a potential therapeutic target for cancer, however, the molecular mechanism of CRGs in coronavirus disease 2019 (COVID-19) infected in DLBCL patients has not been reported yet. Therefore, our research objective is first to elucidate the mechanism and role of CRGs in COVID-19. Secondly, we conducted univariate and multivariate analysis and machine learning to screen for CRGs with common expression differences in COVID-19 and DLBCL...

Although increased aerobic glycolysis is common in various cancers, pancreatic ductal adenocarcinoma (PDAC) cells can survive a state of glycolysis suppression. We aimed to identify potential therapeutic targets in glycolysis-suppressed PDAC cells. By screening anticancer metabolic compounds, we identified SP-2509, an inhibitor of lysine-specific histone demethylase 1A (LSD1), which dramatically decreased the growth of PDAC PANC-1 cells and showed an anti-tumoral effect in tumor-bearing mice. The growth of glycolysis-suppressed PANC-1 cells was also inhibited by another LSD1 inhibitor, OG-L002...

The histone lysine demethylase KDM5B is implicated in recessive intellectual disability disorders and heterozygous, protein truncating variants in KDM5B are associated with reduced cognitive function in the population. The KDM5 family of lysine demethylases has developmental and homeostatic functions in the brain, some of which appear to be independent of lysine demethylase activity. To determine the functions of KDM5B in hippocampus-dependent learning and memory, we first studied male and female mice homozygous for a Kdm5b Δ ARID allele that lacks demethylase activity...

Histone methylation plays crucial roles in regulating chromatin structure and gene transcription in epigenetic modifications. Lysine-specific demethylase 1 (LSD1), the first identified histone demethylase, is universally overexpressed in various diseases. LSD1 dysregulation is closely associated with cancer, viral infections, and neurodegenerative diseases, etc., making it a promising therapeutic target. Several LSD1 inhibitors and two small-molecule degraders (UM171 and BEA-17) have entered the clinical stage...

Current cancer therapy can be effective, but the development of drug resistant disease is the usual outcome. These drugs can eliminate most of the tumor burden but often fail to eliminate the rare, "Drug Tolerant Persister" (DTP) cell subpopulations in residual tumors, which can be referred to as "Persister" cells. Therefore, novel therapeutic agents specifically targeting or preventing the development of drug-resistant tumors mediated by the remaining persister cells subpopulations are needed. Since approximately ninety percent of cancer-related deaths occur because of the eventual development of drug resistance, identifying, and dissecting the biology of the persister cells is essential for the creation of drugs to target them...

Congenital infection caused by vertical transmission of microsporidia N. bombycis can result in severe economic losses in the silkworm-rearing industry. Whole-transcriptome analyses have revealed non-coding RNAs and their regulatory networks in N. bombycis infected embryos and larvae. However, transcriptomic changes in the microsporidia proliferation and host responses in congenitally infected embryos and larvae remains unclear. Here, we simultaneously compared the transcriptomes of N. bombycis and its host B...

The transcription factor Growth Factor Independence 1B (GFI1B) recruits Lysine Specific Demethylase 1 A (LSD1/KDM1A) to stimulate gene programs relevant for megakaryocyte and platelet biology. Inherited pathogenic GFI1B variants result in thrombocytopenia and bleeding propensities with varying intensity. Whether these affect similar gene programs is unknow. Here we studied transcriptomic effects of four patient-derived GFI1B variants (GFI1BT174N ,H181Y ,R184P ,Q287* ) in MEG01 megakaryoblasts. Compared to normal GFI1B, each variant affected different gene programs with GFI1BQ287* uniquely failing to repress myeloid traits...

BACKGROUND/AIM: Lenvatinib, a multikinase inhibitor, has become a second-line treatment option for unresectable liver cancer, while its monotherapy response rate is limited. Hence, we aim to investigate whether one of the epigenetic inhibitors will be synthetic lethal with Lenvatinib in liver cancer cells. MATERIALS AND METHODS: We performed high-throughput drug screening in combination with Lenvatinib. And we employed CCK-8-based Bliss Synergy Score analysis, colony formation and western blotting to confirm our screening results in both HepG2 and HCCC9810 cells...

In the present work, physio-biochemical and DNA methylation analysis were conducted in wheat (Triticum aestivum L.) cultivars "Bolani" (drought-tolerant) and "Sistan" (drought-sensitive) during drought treatments: well-watered (at 90% field capacity (FC)), mild stress (at 50% FC, and severe stress (at 25% FC). During severe stress, O2 •- and H2 O2 content in cultivar Sistan showed significant increase (by 1.3 and 2.5-fold, respectively) relative to cultivar Bolani. In Bolani, the increased levels of radical scavenging activity (by 32%), glycine betaine (GB) (by 11...

Recent studies have consistently demonstrated that the regulation of chromatin and gene transcription plays a pivotal role in the pathogenesis of neurodevelopmental disorders. Among many genes involved in these pathways, KMT2C, encoding one of the six known histone H3 lysine 4 (H3K4) methyltransferases in humans and rodents, was identified as a gene whose heterozygous loss-of-function variants are causally associated with autism spectrum disorder (ASD) and the Kleefstra syndrome phenotypic spectrum. However, little is known about how KMT2C haploinsufficiency causes neurodevelopmental deficits and how these conditions can be treated...

Cellular senescence assumes pivotal roles in various diseases through the secretion of proinflammatory factors. Despite extensive investigations into vascular senescence associated with aging and degenerative diseases, the molecular mechanisms governing microvascular endothelial cell senescence induced by traumatic stress, particularly its involvement in senescence-induced inflammation, remain insufficiently elucidated. In this study, we present a comprehensive demonstration and characterization of microvascular endothelial cell senescence induced by spinal cord injury (SCI)...

Lysine-specific histone demethylase 5A (KDM5A) is known to facilitate proliferation in cancer cells and maintain stemness to repress the astrocytic differentiation of neural stem cells (NSCs). In the study presented here, we investigated the effect of a KDM5 inhibitor, CPI-455, on NSC fate control. CPI-455 induced astrocytogenesis in NSCs during differentiation. Kdm5a , but not Kdm5c , knockdown induced glial fibrillary acidic protein ( Gfap ) transcription. CPI-455 induced signal transducer and activator of transcription 3, increased bone morphogenetic protein 2 expression, and enhanced mothers against decapentaplegic homolog 1/5/9 phosphorylation...