Lysine Demethylase 2A Research Articles

HDAC1-mediated regulation of KDM1A in pemphigus vulgaris: unlocking mechanisms on ERK pathway activation and cohesion loss.

Pemphigus vulgaris (PV) is an autoimmune skin disorder characterized by the loss of cell cohesion, with the histone deacetylase 1 (HDAC1) and lysine demethylase 1A (KDM1A) playing critical roles in its pathogenesis. This study aimed to elucidate the molecular mechanisms behind PV, focusing on the function of HDAC1 and KDM1A in disease onset and progression. Based on in vitro and in vivo PV models, we observed a significant increase in HDAC1 mRNA and protein levels in skin tissues of PV patients. Inhibition of HDAC1 ameliorated cell damage and reduced the loss of cell cohesion in human epidermal keratinocytes (HEKs) induced by PV-IgG. Our findings suggest that HDAC1 regulates KDM1A expression through deacetylation, with a notable deficiency in KDM1A expression in PV. Overexpression of KDM1A mitigated cell damage and cohesion loss. The extracellular signal-regulated kinase (ERK) pathway serves as a downstream executor of the HDAC1/KDM1A axis. Inhibiting HDAC1 and increasing KDM1A expression suppressed ERK phosphorylation, reducing PV-related apoptosis. These insights provide a new perspective on treating PV, highlighting the therapeutic potential of targeting HDAC1 expression. The regulatory mechanism of the HDAC1/KDM1A/ERK axis offers crucial clues for understanding PV pathogenesis and developing novel treatments.

Estrogen Enhances FDFT1 Expression in Theca Cells of Chicken Hierarchical Ovarian Follicles by Increasing LSD1Ser54p Level Through GSK3β Phosphorylation at 216th Tyrosine

The development of chicken ovarian follicles involves two key stages of primordial follicle recruitment and follicle selection that are tightly regulated by multiple reproductive hormones and cytokines. Our previous study revealed an estrogen-stimulated increase in the phosphorylation level of serine at position 54 of lysine demethylase 1A (LSD1Ser54p) in the theca cells of chicken hierarchical ovarian follicles (Post-TCs). In this study, we further found that the upregulation of LSD1Ser54p by estrogen was performed by glycogen synthase kinase 3 beta (GSK3β) and that GSK3β promoted LSD1Ser54p levels by directly binding to the SWIRM and AOL1 domains of LSD1. Upon estrogen stimulation, the phosphorylation level of tyrosine at position 216 of GSK3β (GSK3βTyr216p) increased, which enhanced the binding between LSD1 and GSK3β. The subsequent transcriptome sequencing on chicken Post-TCs treated with estrogen and CUT&RUN sequencing against the LSD1Ser54p protein revealed that the expression of the farnesyl-diphosphate farnesyltransferase 1 (FDFT1) gene was simultaneously upregulated by estrogen, GSK3β, and LSD1Ser54p. Moreover, the overexpression of FDFT1 further promoted cholesterol biosynthesis in chicken Post-TCs. In short, the findings of this study suggest that estrogen-induced tyrosine phosphorylation at position 216 of GSK3β can upregulate the level of LSD1Ser54p, leading to the activation of FDFT1 expression and subsequently promoting cholesterol biosynthesis in chicken Post-TCs, which may in turn enhance estrogen synthesis.

Apigenin inhibits lipid metabolism of hepatocellular carcinoma cells by targeting the histone demethylase KDM1A

BackgroundThe development of cancer is accompanied by metabolic reprogramming, and the liver serves as a central hub for lipid transportation. Apigenin, a plant-derived flavonoid, demonstrates potent anticancer properties across various cancer types and exhibits promising potential as a therapeutic agent for cancer treatment. However, there are limited studies focusing on the downstream targets of apigenin. Moreover, there are few reports on the impact of apigenin in lipid metabolism within liver cancer cells. PurposeThe objective is to elucidate the metabolic mechanism underlying the inhibitory effect of apigenin on liver cancer progression, search for downstream targets and provide reliable data support for the clinical trials of apigenin. MethodsAnticancer effects of apigenin were detected at cellular and molecular levels in vitro, and downstream targets of apigenin, especially metabolic pathway genes, were analyzed by transcriptome. Next, the downstream target of apigenin was verified and the biological function of the downstream target was examined. Finally, the downstream target of apigenin was further verified by restoring target gene expression. ResultsCellular molecular experiments showed that Apigenin inhibited the proliferation, migration, invasion and lipid metabolism of hepatocellular carcinoma (HCC) cells. Transcriptome analysis showed apigenin widely regulates histone demethylase, particularly histone H3K4 lysine demethylase 1A (KDM1A). Apigenin treatment inhibited the expression of KDM1A protein and mRNA levels in liver cancer cells, molecular docking predicted the interaction between apigenin and KDM1A. Furthermore, downregulation KDM1A inhibited the proliferation and lipid metabolism of HCC cells, in the same way, overexpressing KDM1A promoted proliferation of HCC cells. Finally, restoring KDM1A expression partially attenuated the effects of apigenin on lipid metabolism in HCC cells. ConclusionIn conclusion, our study provides compelling evidence that apigenin inhibits liver cancer progression and elucidates its mechanism of action in regulating lipid metabolism. Specifically, we find that apigenin suppresses the progression of HCC cells by downregulating genes involved in lipid metabolism. Additionally, our results indicate that KDM1A acts as a downstream target of apigenin in the inhibition of lipid metabolism in HCC. These findings offer experimental support for the potential use of apigenin as a therapeutic agent for liver cancer, highlighting its relevance in future clinical applications.

Inactivation of KDM6A promotes the progression of colorectal cancer by enhancing the glycolysis

KDM6A (lysine demethylase 6A) has been reported to undergo inactivating mutations in colorectal cancer, but its function in the progression of colorectal cancer has not been evaluated using animal models of colorectal cancer. In this study, we found that knocking out KDM6A expression in mouse intestinal epithelium increased the length of villus and crypt, promoting the development of AOM (azoxymethane)/DSS (dextran sulfate sodium salt)-induced colorectal cancer. On the other hand, knocking down KDM6A expression promoted the growth of colorectal cancer cells. In molecular mechanism studies, we found that KDM6A interacts with HIF-1α; knocking down KDM6A promotes the binding of HIF-1α to the LDHA promoter, thereby promoting LDHA expression and lactate production, enhancing glycolysis. Knocking down LDHA reversed the malignant phenotype caused by KDM6A expression loss. In summary, this study using animal models revealed that KDM6A loss promotes the progression of colorectal cancer through reprogramming the metabolism of the colorectal cancer cells, suggesting that restoring the function of KDM6A is likely to be one of the strategies for colorectal cancer treatment.

Beta cell-derived exosomes from KDM6A KO mice enhances glucose uptake via upregulation of GLUT4 in skeletal muscles and adipocytes

Exosomes are small extracellular vesicles secreted by various cell types which have gained prominence as potent mediators of intercellular communication. Beta cells play a critical role in glucose homeostasis through the production and secretion of insulin. Lysine demethylase 6A (KDM6A) belongs to the KDM6 family of histone H3 lysine 27 (H3K27) demethylases which is important for the development of various organs. Our previous study showed that beta cell-specific knockout of KDM6A increased glucose tolerance and enhanced peripheral insulin sensitivity in mice. The aim of this study is to investigate whether beta cell-derived exosomes, particularly those derived from KDM6A knockout (INS1-KDM6A-KO) beta cells, regulates glucose uptake in skeletal muscles and adipocytes. We found that serum exosome concentrations were increased significantly in the INS1-KDM6A-KO group. Skeletal muscles were isolated from WT and INS1-KDM6A-K mice. GLUT4 protein expression was upregulated in skeletal muscles in INS1-KDM6A-KO mice. Moreover, pancreatic islets isolated from the INS1-KDM6A-KO mice exhibited a notable increase in exosome release. Interestingly, exosomes from beta islets largely enhanced glucose uptake in cultured skeletal muscle cells and 3T3-L1 adipocytes. Meanwhile, beta cell-derived exosomes from KDM6A-KO mice upregulated GLUT4 in NOR-10 cells, especially in the presence of insulin. The findings suggest that beta cell-derived exosomes may play an important role in KDM6A deficiency-induced enhancement in insulin sensitivity likely via upregulation of GLUT4 in skeletal muscle cells and adipocytes. This work was supported by NIH R01 Grants - HL154147 and AG062375. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Kdm6a-CNN1 axis orchestrates epigenetic control of trauma-induced spinal cord microvascular endothelial cell senescence to balance neuroinflammation for improved neurological repair

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 demethylase 6A (Kdm6a), commonly known as UTX, emerges as a crucial regulator of cell senescence in injured spinal cord microvascular endothelial cells (SCMECs). Upregulation of UTX induces senescence in SCMECs, leading to an amplified release of proinflammatory factors, specifically the senescence-associated secretory phenotype (SASP) components, thereby modulating the inflammatory microenvironment. Conversely, the deletion of UTX in endothelial cells shields SCMECs against senescence, mitigates the release of proinflammatory SASP factors, and promotes neurological functional recovery after SCI. UTX forms an epigenetic regulatory axis by binding to calponin 1 (CNN1), orchestrating trauma-induced SCMECs senescence and SASP secretion, thereby influencing neuroinflammation and neurological functional repair. Furthermore, local delivery of a senolytic drug reduces senescent SCMECs and suppresses proinflammatory SASP secretion, reinstating a local regenerative microenvironment and enhancing functional repair after SCI. In conclusion, targeting the UTX-CNN1 epigenetic axis to prevent trauma-induced SCMECs senescence holds the potential to inhibit SASP secretion, alleviate neuroinflammation, and provide a novel treatment strategy for SCI repair.

Sex-specific difference in phenotype of Kabuki syndrome type 2 patients: a matched case-control study.

Kabuki syndrome (KS) is a monogenic disorder leading to special facial features, mental retardation, and multiple system malformations. Lysine demethylase 6A, (KDM6A, MIM*300128) is the pathogenic gene of Kabuki syndrome type 2 (KS2, MIM#300867), which accounts for only 5%-8% of KS. Previous studies suggested that female patients with KS2 may have a milder phenotype. We summarized the phenotype and genotype of KS2 patients who were diagnosed in Shanghai Children's Medical Center since July 2017 and conducted a 1:3 matched case-control study according to age and sex to investigate sex-specific differences between patients with and without KS2. There were 12 KS2 cases in this study, and 8 of them matched with 24 controls. The intelligence quotient (IQ) score of the case group was significantly lower than that of the control group (P < 0.001). In addition, both the incidence of intellectual disability (ID) (IQ < 70) and moderate-to-severe ID (IQ < 55) were significantly higher in the case group than those in the control group. No sex-specific difference was found in the incidence of ID or moderate-to-severe ID between the female cases and female controls, whereas there was a significant difference between male cases and male controls. Furthermore, the rate of moderate-to-severe ID and congenital heart disease (CHD) was significantly higher in the male group than that in the female group. Our results showed that a sex-specific difference was exhibited in the clinical phenotypes of KS2 patients. The incidence of CHD was higher in male patients, and mental retardation was significantly impaired. However, the female patients' phenotype was mild.

KDM1A genotyping and expression in 146 sporadic somatotroph pituitary adenomas.

A paradoxical increase of growth hormone (GH) following oral glucose load has been described in ∼30% of patients with acromegaly and has been related to the ectopic expression of the glucose-dependent insulinotropic polypeptide (GIP) receptor (GIPR) in somatotropinomas. Recently, we identified germline pathogenic variants and somatic loss of heterozygosity of lysine demethylase 1A (KDM1A) in patients with GIP-dependent primary bilateral macronodular adrenal hyperplasia with Cushing's syndrome. The ectopic expression of GIPR in both adrenal and pituitary lesions suggests a common molecular mechanism. We aimed to analyze KDM1A gene sequence and KDM1A and GIPR expressions in somatotroph pituitary adenomas. We conducted a cohort study at university hospitals in France and in Italy. We collected pituitary adenoma specimens from acromegalic patients who had undergone pituitary surgery. We performed targeted exome sequencing (gene panel analysis) and array-comparative genomic hybridization on somatic DNA derived from adenomas and performed droplet digital PCR on adenoma samples to quantify KDM1A and GIPR expressions. One hundred and forty-six patients with sporadic acromegaly were studied; 72.6% presented unsuppressed classical GH response, whereas 27.4% displayed a paradoxical rise in GH after oral glucose load. We did not identify any pathogenic variant in the KDM1A gene in the adenomas of these patients. However, we identified a recurrent 1p deletion encompassing the KDM1A locus in 29 adenomas and observed a higher prevalence of paradoxical GH rise (P = .0166), lower KDM1A expression (4.47 ± 2.49 vs 8.56 ± 5.62, P < .0001), and higher GIPR expression (1.09 ± 0.92 vs 0.43 ± 0.51, P = .0012) in adenomas from patients with KDM1A haploinsufficiency compared with those with 2 KDM1A copies. Unlike in GIP-dependent primary bilateral macronodular adrenal hyperplasia, KDM1A genetic variations are not the cause of GIPR expression in somatotroph pituitary adenomas. Recurrent KDM1A haploinsufficiency, more frequently observed in GIPR-expressing adenomas, could be responsible for decreased KDM1A function resulting in transcriptional derepression on the GIPR locus.

Knockout of KDM3A in MDA-MB-231 breast cancer cells inhibits tumor malignancy and promotes apoptosis.

The histone lysine demethylase 3A (KDM3A) is vital for the regulation of cancer physiology and pathophysiology. The purpose of this study was to investigate the effect of KDM3A expression with triple-negative breast cancer (TNBC) invasion and metastasis. In our results, knockout of KDM3A in TNBC MDA-MB-231 cells promoted apoptosis and inhibited the proliferation, invasion and metastasis of MDA-MB-231 cells. In addition, we found that in vivo experiments indicated that the growth, invasion and metastasis of metastatic neoplasms were significantly inhibited by knockout of KDM3A in a TNBC metastasis model. These findings suggest that KDM3A may be a potential therapeutic target for the treatment and prevention of TNBC, providing a critical theoretical basis for the effective prevention or treatment of breast cancer disease.

KDM6A Promotes Angiogenesis, Migration, and Invasion of Pancreatic Cancer by Activating LAMP3.

Lysine demethylase 6A (KDM6A) is abnormally expressed in various cancer. This study aimed to investigate the potential of KDM6A in pancreatic cancer (PC). mRNA expression was calculated by reverse transcription quantitative real-time polymerase chain reaction (RT-qPCR). Protein expression was detected by Western blot. Cell viability was measured by Cell Counting Kit (CCK-8) assay. Cell angiogenesis was determined by tube formation assay. Cell migration and invasion were determined by Transwell assay. We found that KDM6A was upregulated in PC patients and cells. Interestingly, KDM6A deficiency inhibited the proliferation and angiogenesis of PC cells. Moreover, KDM6A knockdown suppressed the migration and invasion of PC cells. Additionally, KDM6A upregulated the expression of lysosomal associated membrane protein 3 (LAMP3) via driving demethylation of H3K27me3. Overexpression of LAMP3 reversed the effects of KDM6A knockdown and contributed to the angiogenesis and aggressiveness of PC cells. In summary, KDM6A-mediated demethylation of tri-methylation at lysine 27 of histone H3 (H3K27me3) promotes the transcription of LAMP3, resulting the angiogenesis and aggressiveness of PC. Therefore, targeting KDM6A may be an anti-angiogenetic strategy for PC.

LncRNA USP2-AS1 facilitates the osteogenic differentiation of bone marrow mesenchymal stem cells by targeting KDM3A/ETS1/USP2 to activate the Wnt/β-catenin signaling pathway

ABSTRACT Human bone marrow mesenchymal stem cells (HBMSCs) can promote new bone formation. Previous studies have proven the ability of long non-coding RNAs (lncRNAs) to modulate the osteogenic differentiation of mesenchymal stem cells. However, the molecular mechanism modulated by lncRNAs in affecting the osteogenic differentiation of HBMSCs remains largely unknown. Thus, this study aims to reveal the role of lncRNA ubiquitin-specific peptidase 2 antisense RNA 1 (USP2-AS1) in regulating the osteogenic differentiation of HBMSCs and investigate its regulatory mechanism. Through bioinformatics analysis and RT-qPCR, we confirmed that USP2-AS1 expression was increased in HBMSCs after culturing in osteogenic differentiation medium (OM-HBMSCs). Moreover, we uncovered that knockdown of USP2-AS1 inhibited the osteogenic differentiation of HBMSCs. Further exploration indicated that USP2-AS1 positively regulated the expression of its nearby gene USP2. Mechanistically, USP2-AS1 recruited lysine demethylase 3A (KDM3A) to stabilize ETS proto-oncogene 1 (ETS1), transcription factor that transcriptionally activated USP2. Additionally, USP2-induced Wnt/β-catenin signalling pathway activation via deubiquitination of β-catenin protein. In summary, our study proved that lncRNA USP2-AS1 facilitates the osteogenic differentiation of HBMSCs by targeting KDM3A/ETS1/USP2 axis to activate the Wnt/β-catenin signalling pathway.

Epigenetic mechanism of miR-26b-5p-enriched MSCs-EVs attenuates spinal cord injury

Mesenchymal stem cells (MSCs) and extracellular vesicles (EVs) are promising therapies for the treatment of spinal cord injury (SCI). This study sought to explore the epigenetic mechanism of miR-26b-5p-enriched MSCs-EVs in SCI. MSCs and MSCs-EVs were isolated and characterized. The SCI rat model was established, followed by Basso-Beattie-Bresnahan scoring and H&E staining. In vitro cell models were established in PC12 cells with lipopolysaccharide (LPS) treatment, followed by cell viability evaluation using CCK-8 assay. The levels of miR-26b-5p, lysine demethylase 6A (KDM6A), NADPH oxidase 4 (NOX4), reactive oxygen species (ROS), and inflammatory factors (TNF-α/IL-1β/IL-6) in tissues and cells were detected. The levels of cy3-lablled miR-26b-5p in tissues and cells were observed by confocal microscopy. The binding of miR-26b-5p to KDM6A 3′UTR and the enrichments of KDM6A and H3K27me3 at the NOX4 promoter were analyzed. MSCs-EVs attenuated motor dysfunction, inflammation, and oxidative stress in SCI rats. MSCs-EVs delivered miR-26b-5p into PC12 cells to reduce LPS-induced inflammation and ROS production and enhance cell viability. miR-26b-5p inhibited KDM6A, and KDM6A reduced H3K27me3 at the NOX4 promoter to promote NOX4. Overexpression of KDM6A or NOX4 reversed the alleviative role of MSCs-EVs in SCI or LPS-induced cell injury. Overall, MSCs-EVs delivered miR-26b-5p into cells to target the KDM6A/NOX4 axis and facilitate the recovery from SCI.

Disruption of the autism gene and chromatin regulator KDM5A alters hippocampal cell identity.

Chromatin regulation plays a pivotal role in establishing and maintaining cellular identity and is one of the top pathways disrupted in autism spectrum disorder (ASD). The hippocampus, composed of distinct cell types, is often affected in patients with ASD. However, the specific hippocampal cell types and their transcriptional programs that are dysregulated in ASD are unknown. Using single-nucleus RNA sequencing, we show that the ASD gene, lysine demethylase 5A (KDM5A), regulates the development of specific subtypes of excitatory and inhibitory neurons. We found that KDM5A is essential for establishing hippocampal cell identity by controlling a differentiation switch early in development. Our findings define a role for the chromatin regulator KDM5A in establishing hippocampal cell identity and contribute to the emerging convergent mechanisms across ASD.

Lysine demethylase 3A in hypoxic macrophages promotes ovarian cancer development through regulation of the vascular endothelial growth factor A/Akt signaling

BackgroundHypoxia is a vital feature of the tumor microenvironment of OC. Previous evidence exposes that tumor-associated macrophages (TAMs) are connected with the development of ovarian cancer (OC), whereas the accurate regulatory mechanism of hypoxic macrophages regulating tumor advancement remains unclear. Herein, we examined whether the lysine demethylase 3 A (KDM3A) in hypoxic macrophages expedited the development of OC cells. MethodsThe contents of hypoxia inducible factor-1α (HIF-1α), CD163, CD80, KDM3A, and p-Akt/Akt were detected by western blot. Genomic Spatial Event 4630, Molecular Signatures Database, and Comparative Toxicogenomics Database were utilized for correlated gene prediction. The OC cells viability was scrutinized by cell counting kit-8 assay. The cell proliferation was inspected by 5-Ethynyl-2′-deoxyuridine assay. The vascular endothelial growth factor A (VEGF) level was detected by Enzyme-linked immunosorbent assay. ResultsM2 polarization of TAMs was associated with poor prognosis in sufferers with OC. The OC sufferers with high level of CD163 or low level of CD80 were linked with poor overall survival and disease specific survival. Hypoxia induced THP-1-derived macrophages M2 polarization. KDM3A was high-expressed in hypoxia induced macrophages. Upregulated KDM3A in hypoxic macrophages facilitated OC cell proliferation. KDM3A upregulation in hypoxic macrophages stimulated Akt signaling activation in OC cells. KDM3A in hypoxic macrophages promoted VEGF secretion to activate Akt signaling in OC cells. VEGF inhibition or Akt signaling inactivation reversed the effects of KDM3A in hypoxic macrophages on OC cells viability and proliferation. ConclusionThe KDM3A content and M2 polarization were enhanced in hypoxic macrophages, and KDM3A in hypoxic macrophages promoted OC development through regulation of the VEGF/Akt signaling pathway.

KDM6A/UTX promotes spermatogenic gene expression across generations and is not required for male fertility†.

Paternal chromatin undergoes extensive structural and epigenetic changes during mammalian spermatogenesis, producing sperm with an epigenome optimized for the transition to embryogenesis. Lysine demethylase 6a (KDM6A, also called UTX) promotes gene activation in part via demethylation of H3K27me3, a developmentally important repressive modification abundant throughout the epigenome of spermatogenic cells and sperm. We previously demonstrated increased cancer risk in genetically wild-type mice derived from a paternal germ line lacking Kdm6a (Kdm6a cKO), indicating a role for KDM6A in regulating heritable epigenetic states. However, the regulatory function of KDM6A during spermatogenesis is not known. Here, we show that Kdm6a is transiently expressed in spermatogenesis, with RNA and protein expression largely limited to late spermatogonia and early meiotic prophase. Kdm6a cKO males do not have defects in fertility or the overall progression of spermatogenesis. However, hundreds of genes are deregulated upon loss of Kdm6a in spermatogenic cells, with a strong bias toward downregulation coinciding with the time when Kdm6a is expressed. Misregulated genes encode factors involved in chromatin organization and regulation of repetitive elements, and a subset of these genes was persistently deregulated in the male germ line across two generations of offspring of Kdm6a cKO males. Genome-wide epigenetic profiling revealed broadening of H3K27me3 peaks in differentiating spermatogonia of Kdm6a cKO mice, suggesting that KDM6A demarcates H3K27me3 domains in the male germ line. Our findings highlight KDM6A as a transcriptional activator in the mammalian male germ line that is dispensable for spermatogenesis but important for safeguarding gene regulatory state intergenerationally.

Expression of lysine demethylase 5a (Kdm5a) influences tumour aggressiveness in murine pancreatic cancer cells

Expression of lysine demethylase 5a (Kdm5a) influences tumour aggressiveness in murine pancreatic cancer cells

Natural products modulating epigenetic mechanisms by affecting histone methylation/demethylation: targeting cancer cells.

Many natural products can exert anticancer or chemopreventive activity by interfering with the cellular epigenetic machinery. While a plethora of studies indicate the relevance of affecting DNA methylation and histone acetylation, the influence on the mechanisms related to histone methylation is often overlooked. This may be associated with the lagging evidence that changes in the action of histone methylation writers and erasers and subsequent alterations in the profile of histone methylation are causally related with carcinogenesis. However, recent animal studies have shown that targeting histone methylation/demethylation affects the course of experimentally induced carcinogenesis. Existing data suggest that numerous natural compounds from different chemical groups, including green tea polyphenols and other flavonoids, curcuminoids, stilbene derivatives, phenolic acids, isothiocyanates, alkaloids and terpenes, can affect the expression and activity of crucial enzymes involved in the methylation and demethylation of histone lysine and arginine residues. These activities have been associated with the modulation of cancer-related gene expression and functional changes, including reduced cell proliferation and migration, and enhanced apoptosis in various cancer models. Most studies focused on the modulation of the expression and/or activity of two proteins - EZH2 (a H3K27 methyltransferase) and LSD1 (a H3K4/9 demethylase), or the effects on the global levels of histone methylation marks by the phytochemicals, but data regarding other histone methyltransferases or demethylases are scarce. While the field still remains relatively unexplored, this review aims to explore the impact of natural products on the enzymes related to histone methylation/demethylation, showing their relevance to carcinogenesis and cancer progression.

OR17-05 Lysine Demethylase KDM1A And Ectopic Expression Of GIP-Receptor In Somatotropinomas Of Patients With Paradoxical Response To Oral Glucose

Abstract Disclosure: F. Chasseloup: None. L. Tosca: None. D. Regazzo: None. A. Proust: None. M. Hage: None. E. Kuhn: None. C. Jublanc: None. K. Mokhtari: None. S. Salenave: None. S. Gaillard: None. F. Parker: None. A. Boch: None. G. Tachdjian: None. P. Chanson: None. J. Bouligand: None. G. Occhi: None. P. Kamenicky: None. Introduction: Paradoxical increase of GH following oral glucose load has been described in ∼30% of patients with acromegaly and has been related to the ectopic expression of the glucose-dependent insulinotropic polypeptide (GIP) receptor (GIPR) in somatotropinomas. Recently, we identified germline pathogenic variants of lysine demethylase 1A (KDM1A) in patients with GIP-dependent primary bilateral macronodular adrenal hyperplasia with Cushing’s syndrome. Most patients also displayed a deletion of chromosome 1p, including the KDM1A locus in their adrenal tissues, resulting in complete loss of KDM1A expression. The ectopic expression of GIPR in both adrenal and pituitary lesions suggests a common molecular mechanism. The aim of our study was to search for genetic abnormalities of KDM1A in somatotroph pituitary adenomas. Methods: We collected somatotropinoma specimens from acromegalic patients followed in two tertiary endocrine centers in France and one in Italy. Somatic DNA was studied by targeted exome NGS and array-CGH. GIPR and KDM1A expression was quantified in the tumors using digital droplet PCR. Results: We included 186 patients: 108 patients (70.6 %) had a classic pathological GH response after oral glucose load, whereas 45 patients (29.4%) displayed a paradoxical rise of GH concentrations. Patients with a paradoxical response displayed higher IGF-1 levels (360 ± 111.8 % above ULN vs. 309.8 ± 107.3 %, p= 0.0130) and less invasive and smaller tumors (14.5 ± 5.58 mm vs. 18.5 ± 8.73 m, p= 0.0066). Amongst the 146 somatotropinoma specimens analyzed by targeted-NGS, no tumor harbored a KDM1A pathogenic variant, and 35 tumors harbored GNAS mutations (6 with and 29 without paradoxical GH responses). We identified a recurrent 1p deletion encompassing the KDM1A locus in 26 tumors, which were more frequently but not exclusively found in patients with paradoxical GH response compared to those with classic GH response. Somatic deletion of one KMD1A allele was associated with lower KDM1A expression (p=4.5e-5) and higher GIPR expression (p=0.0005). Discussion: Unlike in GIP-dependent PBMAH, we did not identify KDM1A genetic variants in a large cohort of acromegalic patients, independently of their GH response pattern to oral glucose loading. We identified recurrent 1p deletion in some tumors. Pituitary adenomas with a loss of one KDM1A copy due to chromosome 1p deletion harbored higher levels of GIPR transcripts than adenomas diploid for the KDM1A locus. If KDM1A haploinsufficiency leads to partial transcriptional derepression at the GIPR locus and a paradoxical rise of GH after glucose load warrants further investigations. Presentation: Saturday, June 17, 2023

KDM2A Deficiency in the Liver Promotes Abnormal Liver Function and Potential Liver Damage.

Dysregulation of metabolic functions in the liver impacts the development of diabetes and metabolic disorders. Normal liver function can be compromised by increased inflammation via the activation of signaling such as nuclear factor (NF)-κB signaling. Notably, we have previously identified lysine demethylase 2A (KDM2A)-as a critical negative regulator of NF-κB. However, there are no studies demonstrating the effect of KDM2A on liver function. Here, we established a novel liver-specific Kdm2a knockout mouse model to evaluate KDM2A's role in liver functions. An inducible hepatic deletion of Kdm2a, Alb-Cre-Kdm2afl/fl (Kdm2a KO), was generated by crossing the Kdm2a floxed mice (Kdm2afl/fl) we established with commercial albumin-Cre transgenic mice (B6.Cg-Tg(Alb-cre)21Mgn/J). We show that under a normal diet, Kdm2a KO mice exhibited increased serum alanine aminotransferase (ALT) activity, L-type triglycerides (TG) levels, and liver glycogen levels vs. WT (Kdm2afl/fl) animals. These changes were further enhanced in Kdm2a liver KO mice in high-fat diet (HFD) conditions. We also observed a significant increase in NF-κB target gene expression in Kdm2a liver KO mice under HFD conditions. Similarly, the KO mice exhibited increased immune cell infiltration. Collectively, these data suggest liver-specific KDM2A deficiency may enhance inflammation in the liver, potentially through NF-κB activation, and lead to liver dysfunction. Our study also suggests that the established Kdm2afl/fl mouse model may serve as a powerful tool for studying liver-related metabolic diseases.

Therapeutic Potential of Targeting Epigenetic Factors HIF-1a and KDM3A in Ovarian Cancer and PCOS

Ovarian cancer and polycystic ovary syndrome (PCOS) are significant health concerns for women, posing challenges in terms of treatment and prognosis. Hypoxia-inducible factor 1 alpha (HIF-1a) and lysine demethylase 3A (KDM3A) have emerged as promising therapeutic targets for both conditions due to their involvement in critical cellular processes. This article explores the therapeutic potential of targeting HIF-1a and KDM3A in ovarian cancer and PCOS, investigating their molecular mechanisms in disease progression, including angiogenesis, cell proliferation, and metabolic dysregulation. Recent preclinical and clinical studies evaluating the effectiveness of HIF-1a and KDM3A inhibitors are discussed, emphasizing their potential as innovative therapeutic strategies. These findings highlight the importance of understanding the complex interplay between HIF-1a, KDM3A, and the pathogenesis of ovarian cancer and PCOS, ultimately facilitating the development of targeted therapies.