RESUMEN
Pancreatic cancer (PC) is a challenging and heterogeneous disease with a high mortality rate. Despite advancements in treatment, the prognosis for PC patients remains poor, with a high chance of disease recurrence. Biomarkers are crucial for diagnosing cancer, predicting patient prognosis and selecting treatments. However, the current lack of effective biomarkers for PC could contribute to the insufficiency of existing treatments. These findings underscore the urgent need to develop novel strategies to fight this disease. This study utilized multiple comprehensive bioinformatic analyses to identify potential therapeutic target genes in PC, focusing on histone lysine demethylases (KDMs). We found that high expression levels of KDM family genes, particularly KDM1A, KDM5A and KDM5B, were associated with improved overall survival in the cohort. Furthermore, the infiltration of various immune cells, including B cells, neutrophils, CD8+ T cells, dendritic cells, and macrophages, was positively correlated with KDM1A, KDM5A, and KDM5B expression. Moreover, MetaCore pathway analysis revealed interesting connections between KDM1A and the cell cycle and proliferation, between KDM5A and DNA damage and double-strand break repair through homologous recombination, and between KDM5B and WNT/ß-catenin signaling. These findings suggest that KDM1A, KDM5A and KDM5B may serve as promising biomarkers and therapeutic targets for PC, a disease of high importance due to its aggressive nature and urgent need for novel biomarkers to improve diagnosis and treatment.
Asunto(s)
Biomarcadores de Tumor , Regulación Neoplásica de la Expresión Génica , Histona Demetilasas con Dominio de Jumonji , Neoplasias Pancreáticas , Humanos , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patología , Neoplasias Pancreáticas/metabolismo , Histona Demetilasas con Dominio de Jumonji/metabolismo , Histona Demetilasas con Dominio de Jumonji/genética , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Pronóstico , Biología Computacional , Proteínas F-Box/metabolismo , Proteínas F-Box/genética , Histona Demetilasas/metabolismo , Histona Demetilasas/genética , Terapia Molecular Dirigida/métodos , Proteína 2 de Unión a Retinoblastoma/metabolismo , Proteína 2 de Unión a Retinoblastoma/genética , Vía de Señalización Wnt/genética , Proliferación Celular/genética , Proteínas Nucleares , Proteínas RepresorasRESUMEN
Lysine-specific histone demethylase 1 (LSD1), which demethylates mono- or di- methylated histone H3 on lysine 4 (H3K4me1/2), is essential for early embryogenesis and development. Here we show that LSD1 is dispensable for mouse embryonic stem cell (ESC) self-renewal but is required for mouse ESC growth and differentiation. Reintroduction of a catalytically-impaired LSD1 (LSD1MUT) recovers the proliferation capability of mouse ESCs, yet the enzymatic activity of LSD1 is essential to ensure proper differentiation. Indeed, increased H3K4me1 in Lsd1 knockout (KO) mouse ESCs does not lead to major changes in global gene expression programs related to stemness. However, ablation of LSD1 but not LSD1MUT results in decreased DNMT1 and UHRF1 proteins coupled to global hypomethylation. We show that both LSD1 and LSD1MUT control protein stability of UHRF1 and DNMT1 through interaction with HDAC1 and the ubiquitin-specific peptidase 7 (USP7), consequently, facilitating the deacetylation and deubiquitination of DNMT1 and UHRF1. Our studies elucidate a mechanism by which LSD1 controls DNA methylation in mouse ESCs, independently of its lysine demethylase activity.
Asunto(s)
Proteínas Potenciadoras de Unión a CCAAT , Diferenciación Celular , ADN (Citosina-5-)-Metiltransferasa 1 , Metilación de ADN , Histona Demetilasas , Ratones Noqueados , Células Madre Embrionarias de Ratones , Ubiquitina-Proteína Ligasas , Animales , Histona Demetilasas/metabolismo , Histona Demetilasas/genética , Ratones , ADN (Citosina-5-)-Metiltransferasa 1/metabolismo , ADN (Citosina-5-)-Metiltransferasa 1/genética , Células Madre Embrionarias de Ratones/metabolismo , Ubiquitina-Proteína Ligasas/metabolismo , Ubiquitina-Proteína Ligasas/genética , Proteínas Potenciadoras de Unión a CCAAT/metabolismo , Proteínas Potenciadoras de Unión a CCAAT/genética , Histona Desacetilasa 1/metabolismo , Histona Desacetilasa 1/genética , Histonas/metabolismo , Proliferación Celular , UbiquitinaciónRESUMEN
Metastasis accounts for almost 90% of breast cancer-related fatalities, making it frequent malignancy and the main reason of tumor mortality globally among women. LSD1 is a histone demethylase, which plays an important role in breast cancer. In order to explore the effect of LSD1 on invasion and migration of breast cancer, we treated breast cancer cells with MCF7 and T47D exosomes knocked down by LSD1, and the invasion and migration of breast cancer cells were significantly enhanced. This phenomenon indicates that LSD1 can inhibit the invasion and migration of breast cancer cells. miR-1290 expression was downregulated in LSD1 knockdown MCF7 exosomes. By analyzing the database of miR-1290 target gene NAT1, we verified that miR-1290 could regulate the expression of NAT1. These data provide fresh insights into the biology of breast cancer therapy by demonstrating how the epigenetic factor LSD1 stimulates the breast cancer cells' invasion and migration via controlling exosomal miRNA.
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Neoplasias de la Mama , Movimiento Celular , Exosomas , Regulación Neoplásica de la Expresión Génica , Histona Demetilasas , MicroARNs , Invasividad Neoplásica , Humanos , Histona Demetilasas/metabolismo , Histona Demetilasas/genética , Neoplasias de la Mama/patología , Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Exosomas/metabolismo , Movimiento Celular/genética , Femenino , MicroARNs/genética , MicroARNs/metabolismo , Línea Celular Tumoral , Células MCF-7RESUMEN
OBJECTIVE: To explore the inhibitory effect ORY-1001, a lysine-specific histone demethylase 1 (LSD1) inhibitor, on growth of glioblastoma (GBM) and the underlying mechanism. METHODS: We analyzed LSD1 expressions in GBM and normal brain tissues based on data from TCGA and HPA databases. Female BALB/c mouse models bearing xenografts derived from U87 cells or cells with lentivirus-mediated LSD1 silencing or Notch overexpression were treated with saline or 400 µg/kg ORY-1001 by gavage every 7 days, and GBM formation and survival time of the mice were recorded. The effect of ORY-1001 on GBM cell viability was assessed, and its effect on LSD1 expression was analyzed with Western blotting. The genes and pathways associated with LSD1 were analyzed using bioinformatics methods. Western blotting and qRT-PCR were used to detect Notch/HES1 pathway expression after LSD1 silencing and ORY-1001 treatment. The impact of ORY-1001 on viability of U87 cells with Notch1 silencing or overexpression was assessed, and the regulatory effects of ORY-1001 on Notch/HES1 pathway were analyzed using chromatin immunoprecipitation assay. RESULTS: A high expression of LSD1 in GBM was negatively correlated with patient survival (P < 0.001). ORY-1001 and LSD1 silencing obviously reduced tumor burden and prolonged the survival time of GBM-bearing mice. ORY-1001 treatment significantly inhibited the viability and dose-dependently decreased LSD1 expression in GBM cells, and such inhibitory effect of ORY-1001 was attenuated by LSD1 silencing. The Notch pathway enriched the differential genes related to LSD1, and Notch/HES1 pathway expression was significantly down-regulated after LSD1 silencing and ORY-1001 treatment. Notch1 overexpression significantly attenuated the anti-tumor effect of ORY-1001 on GBM. Mechanistically, ORY-1001 disrupted the interaction between LSD1 and the Notch pathway target genes including Notch3, HES1 and CR2. CONCLUSION: ORY-1001 down-regulates the Notch/HES1 pathway by inhibiting LSD1 expression to suppress the growth of GBM in mice.
Asunto(s)
Proliferación Celular , Glioblastoma , Histona Demetilasas , Ratones Endogámicos BALB C , Factor de Transcripción HES-1 , Histona Demetilasas/metabolismo , Histona Demetilasas/genética , Animales , Glioblastoma/metabolismo , Glioblastoma/patología , Glioblastoma/genética , Ratones , Línea Celular Tumoral , Femenino , Factor de Transcripción HES-1/metabolismo , Factor de Transcripción HES-1/genética , Humanos , Proliferación Celular/efectos de los fármacos , Transducción de Señal , Receptores Notch/metabolismo , Regulación hacia Abajo , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologíaRESUMEN
OBJECTIVE: To analyze the lymphocyte subsets in individuals with Kabuki syndrome for better characterizing the immunological phenotype of this rare congenital disorder. METHODS: We characterized the immunological profile including B-, T- and natural killer-cell subsets in a series (N = 18) of individuals with Kabuki syndrome. RESULTS: All 18 individuals underwent genetic analysis: 15 had a variant in KMT2D and 3 a variant in KDM6A. Eleven of the 18 individuals (61%) had recurrent infections and 9 (50%) respiratory infections. Three (17%) had autoimmune diseases. On immunological analysis, 6 (33%) had CD4 T-cell lymphopenia, which was preferentially associated with the KMT2D truncating variant (5/9 individuals). Eight of 18 individuals (44%) had a humoral deficiency and eight (44%) had B lymphopenia. We found abnormal distributions of T-cell subsets, especially a frequent decrease in recent thymic emigrant CD4 + naive T-cell count in 13/16 individuals (81%). CONCLUSION: The immunological features of Kabuki syndrome showed variable immune disorders with CD4 + T-cell deficiency in one third of cases, which had not been previously reported. In particular, we found a reduction in recent thymic emigrant naïve CD4 + T-cell count in 13 of 16 individuals, representing a novel finding that had not previously been reported.
Asunto(s)
Anomalías Múltiples , Proteínas de Unión al ADN , Cara , Histona Demetilasas , Proteínas de Neoplasias , Enfermedades Vestibulares , Humanos , Enfermedades Vestibulares/genética , Enfermedades Vestibulares/inmunología , Cara/anomalías , Femenino , Masculino , Anomalías Múltiples/genética , Anomalías Múltiples/inmunología , Niño , Proteínas de Unión al ADN/genética , Adolescente , Histona Demetilasas/genética , Preescolar , Adulto , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/inmunología , Adulto Joven , Lactante , Linfopenia/inmunología , Linfopenia/genética , Fenotipo , Enfermedades Hematológicas/genética , Enfermedades Hematológicas/inmunología , Mutación , Subgrupos Linfocitarios/inmunología , Subgrupos Linfocitarios/metabolismo , InmunofenotipificaciónRESUMEN
Intervertebral disc disease (IDD) is a debilitating spine condition that can be caused by intervertebral disc (IVD) damage which progresses towards IVD degeneration and dysfunction. Recently, human pluripotent stem cells (hPSCs) were recognized as a valuable resource for cell-based regenerative medicine in skeletal diseases. Therefore, adult somatic cells reprogrammed into human induced pluripotent stem cells (hiPSCs) represent an attractive cell source for the derivation of notochordal-like cells (NCs) as a first step towards the development of a regenerative therapy for IDD. Utilizing a differentiation method involving treatment with a four-factor cocktail targeting the BMP, FGF, retinoic acid, and Wnt signaling pathways, we differentiate CRISPR/Cas9-generated mCherry-reporter knock-in hiPSCs into notochordal-like cells. Comprehensive analysis of transcriptomic changes throughout the differentiation process identified regulation of histone methylation as a pivotal driver facilitating the differentiation of hiPSCs into notochordal-like cells. We further provide evidence that specific inhibition of histone demethylases KDM2A and KDM7A/B enhanced the lineage commitment of hiPSCs towards notochordal-like cells. Our results suggest that inhibition of KDMs could be leveraged to alter the epigenetic landscape of hiPSCs to control notochord-specific gene expression. Thus, our study highlights the importance of epigenetic regulators in stem cell-based regenerative approaches for the treatment of disc degeneration.
Asunto(s)
Diferenciación Celular , Células Madre Pluripotentes Inducidas , Histona Demetilasas con Dominio de Jumonji , Notocorda , Humanos , Células Madre Pluripotentes Inducidas/metabolismo , Células Madre Pluripotentes Inducidas/citología , Notocorda/metabolismo , Notocorda/citología , Histona Demetilasas con Dominio de Jumonji/metabolismo , Histona Demetilasas con Dominio de Jumonji/genética , Histona Demetilasas/metabolismo , Histona Demetilasas/genética , Proteínas F-BoxRESUMEN
BACKGROUND: Urinary bladder cancer, is the 10th most common global cancer, diagnosed in over 600,000 people causing 200,000 deaths annually. Artemisinin and its derivatives are safe compounds that have recently been proven to possess potent anti-tumor effects in vivo, through inhibition of cancer cell growth. The aim of this study is to assess the efficiency of artemisinin as a cancer treatment alone and as a pre-treatment fore cisplatin therapy for high grade urothelial carcinoma. METHODS: Sixty male albino mice were divided into six groups, and BBN was used to induce urinary bladder cancer. Blood samples were tested for renal functions and complete blood counts, kidney and urinary bladder tissues were harvested for histopathological examination. Total RNAs from urinary bladder tissues was collected, and gene expression of FGFR3, HRAS, P53, and KDM6A was quantified using qRT-PCR. RESULTS: Compared to the induced cancer group, the results revealed that FGFR3 expression levels were down-regulated in the induced cancer group treated by artemisinin only and the induced cancer group pre-treated with artemisinin prior to cisplatin by ~ 0.86-fold and 0.4-folds, respectively, aligning with HRAS down-regulation by ~ 9.54-fold and 9.05-fold, respectively. Whereas, P53 expression levels were up-regulated by ~ 0.68-fold and 0.84-fold, respectively, in parallel with KDM6A expression, which is up-regulated by ~ 0.95-folds and 5.27-folds, respectively. Also, serum creatinine and urea levels decreased significantly in the induced cancer group treated by artemisinin alone and the induced cancer group pre-treated with artemisinin prior to cisplatin, whereas the induced cancer group treated by cisplatin their levels increased significantly. Moreover, Hb, PLT, RBC, and WBC counts improved in both cancer groups treated by artemisinin alone and pre-treated with artemisinin prior to cisplatin. Histologically, in kidney tissues, artemisinin pre-treatment significantly reduced renal injury caused by cisplatin. While Artemisinin treatment for cancer in bladder tissues reverted invasive urothelial carcinoma to moderate urothelial dysplasia. CONCLUSIONS: This study indicates that artemisinin demonstrated a significant effect in reversal of the multi-step carcinogenesis process of high grade urothelial carcinoma and could enhance the effect of cisplatin therapy using artemisinin pre-treatment.
Asunto(s)
Artemisininas , Cisplatino , Regulación Neoplásica de la Expresión Génica , Histona Demetilasas , Receptor Tipo 3 de Factor de Crecimiento de Fibroblastos , Proteína p53 Supresora de Tumor , Neoplasias de la Vejiga Urinaria , Animales , Cisplatino/farmacología , Cisplatino/uso terapéutico , Masculino , Artemisininas/farmacología , Artemisininas/uso terapéutico , Receptor Tipo 3 de Factor de Crecimiento de Fibroblastos/genética , Receptor Tipo 3 de Factor de Crecimiento de Fibroblastos/metabolismo , Ratones , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Neoplasias de la Vejiga Urinaria/genética , Neoplasias de la Vejiga Urinaria/patología , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/metabolismo , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Histona Demetilasas/metabolismo , Histona Demetilasas/genética , Proteínas Proto-Oncogénicas p21(ras)/genética , Humanos , Modelos Animales de Enfermedad , Antineoplásicos/farmacología , Antineoplásicos/uso terapéuticoRESUMEN
Radiotherapy (RT) for prostate cancer has been associated with an increased risk for the development of bladder cancer. We aimed to integrate clinical and genomic data to better understand the development of RT-associated bladder cancer. A retrospective analysis was performed to identify control patients (CTRL; n = 41) and patients with RT-associated bladder cancer (n = 41). RT- and CTRL-specific features were then identified through integration and analysis of the genomic sequencing data and clinical variables. RT-associated bladder tumors were significantly enriched for alterations in KDM6A and ATM, whereas CTRL tumors were enriched for CDKN2A mutation. Globally, there were an increased number of variants within RT tumors, albeit at a lower variant allele frequency. Mutational signature analysis revealed three predominate motif patterns, with similarity to SBS2/13 (APOBEC3A), SBS5 (ERCC2/smoking), and SBS6/15 (MMR). Poor prognostic factors in the RT cohort include a short tumor latency, smoking status, the presence of the smoking and X-ray therapy mutational signatures, and CDKN2A copy number loss. Based on the clinical and genomic findings, we suggest at least two potential pathways leading to RT-associated bladder cancer: The first occurs in the setting of field cancerization related to smoking or preexisting genetic alterations and leads to the development of more aggressive bladder tumors, and the second involves RT initiating the oncogenic process in otherwise healthy urothelium, leading to a longer latency and less aggressive disease. SIGNIFICANCE: Clinicogenomic analysis of radiation-associated bladder cancer uncovered mutational signatures that, in addition to a short tumor latency, smoking, and CDKN2A loss, are associated with a poor outcome. These clinical and genomic features provide a potential method to identify patients with prostate cancer who are at an increased risk for the development of aggressive bladder cancer following prostate RT.
Asunto(s)
Inhibidor p16 de la Quinasa Dependiente de Ciclina , Mutación , Neoplasias de la Vejiga Urinaria , Humanos , Neoplasias de la Vejiga Urinaria/genética , Neoplasias de la Vejiga Urinaria/radioterapia , Neoplasias de la Vejiga Urinaria/etiología , Masculino , Pronóstico , Inhibidor p16 de la Quinasa Dependiente de Ciclina/genética , Anciano , Estudios Retrospectivos , Persona de Mediana Edad , Femenino , Histona Demetilasas/genética , Proteínas de la Ataxia Telangiectasia Mutada/genética , Neoplasias Inducidas por Radiación/genética , Neoplasias Inducidas por Radiación/epidemiología , Anciano de 80 o más AñosRESUMEN
Histone lysine-specific demethylase 1 (LSD1) is frequently overexpressed in triple negative breast cancer (TNBC), which is associated with worse clinical outcome in TNBC patients. However, the underlying mechanisms by which LSD1 promotes TNBC progression remain to be identified. We recently established a genetically engineered murine model by crossing mammary gland conditional LSD1 knockout mice with Brca1-deficient mice to explore the role of LSD1 in TNBC pathogenesis. Cre-mediated Brca1 loss led to higher incidence of tumor formation in mouse mammary glands, which was hindered by concurrent depletion of LSD1, indicating a critical role of LSD1 in promoting Brca1-deficient tumors. We also demonstrated that the silencing of a tumor suppressor gene, Tissue Factor Pathway Inhibitor 2 (TFPI2), is functionally associated with LSD1-mediated TNBC progression. Mouse Brca1-deficient tumors exhibited elevated LSD1 expression and decreased TFPI2 level compared to normal mammary tissues. Analysis of TCGA database revealed that TFPI2 expression is significantly lower in aggressive ER-negative or basal-like BC. Restoration of TFPI2 through LSD1 inhibition increased H3K4me2 enrichment at the TFPI2 promoter, suppressed tumor progression, and enhanced antitumor efficacy of chemotherapeutic agent. Induction of TFPI2 by LSD1 ablation downregulates activity of matrix metalloproteinases (MMPs) that in turn increases the level of cytotoxic T lymphocyte attracting chemokines in tumor environment, leading to enhanced tumor infiltration of CD8+ T cells. Moreover, induction of TFPI2 potentiates antitumor effect of LSD1 inhibitor and immune checkpoint blockade in poorly immunogenic TNBC. Together, our study identifies previously unrecognized roles of TFPI2 in LSD1-mediated TNBC progression, therapeutic response, and immunogenic effects.
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Progresión de la Enfermedad , Glicoproteínas , Histona Demetilasas , Neoplasias de la Mama Triple Negativas , Animales , Histona Demetilasas/metabolismo , Histona Demetilasas/genética , Femenino , Ratones , Humanos , Neoplasias de la Mama Triple Negativas/patología , Neoplasias de la Mama Triple Negativas/inmunología , Neoplasias de la Mama Triple Negativas/genética , Neoplasias de la Mama Triple Negativas/metabolismo , Glicoproteínas/genética , Glicoproteínas/metabolismo , Ratones Noqueados , Línea Celular Tumoral , Regulación Neoplásica de la Expresión Génica , Proteína BRCA1/genéticaRESUMEN
BACKGROUND: Primary bilateral macronodular adrenal hyperplasia (PBMAH) is a rare cause of Cushing's syndrome. Individuals with PBMAH and glucose-dependent insulinotropic polypeptide (GIP)-dependent Cushing's syndrome due to ectopic expression of the GIP receptor (GIPR) typically harbor inactivating KDM1A sequence variants. Primary unilateral macronodular adrenal hyperplasia (PUMAH) with concomitant glucocorticoid and androgen excess has never been encountered or studied. METHODS: We investigated a woman with a large, heterogeneous adrenal mass and severe adrenocorticotropic hormone-independent glucocorticoid and androgen excess, a biochemical presentation typically suggestive of adrenocortical carcinoma. The patient presented during pregnancy (22nd week of gestation) and reported an 18-month history of oligomenorrhea, hirsutism, and weight gain. We undertook an exploratory study with detailed histopathological and genetic analysis of the resected adrenal mass and leukocyte DNA collected from the patient and her parents. RESULTS: Histopathology revealed benign macronodular adrenal hyperplasia. Imaging showed a persistently normal contralateral adrenal gland. Whole-exome sequencing of 4 representative nodules detected KDM1A germline variants, benign NM_001009999.3:c.136G > A:p.G46S, and likely pathogenic NM_001009999.3:exon6:c.865_866del:p.R289Dfs*7. Copy number variation analysis demonstrated an additional somatic loss of the KDM1A wild-type allele on chromosome 1p36.12 in all nodules. RNA sequencing of a representative nodule showed low/absent KDM1A expression and increased GIPR expression compared with 52 unilateral sporadic adenomas and 4 normal adrenal glands. Luteinizing hormone/chorionic gonadotropin receptor expression was normal. Sanger sequencing confirmed heterozygous KDM1A variants in both parents (father: p.R289Dfs*7 and mother: p.G46S) who showed no clinical features suggestive of glucocorticoid or androgen excess. CONCLUSIONS: We investigated the first PUMAH associated with severe Cushing's syndrome and concomitant androgen excess, suggesting pathogenic mechanisms involving KDM1A.
Asunto(s)
Síndrome de Cushing , Histona Demetilasas , Humanos , Femenino , Adulto , Histona Demetilasas/genética , Histona Demetilasas/metabolismo , Síndrome de Cushing/genética , Síndrome de Cushing/patología , Síndrome de Cushing/metabolismo , Glucocorticoides , Embarazo , Andrógenos/metabolismo , Glándulas Suprarrenales/patología , Glándulas Suprarrenales/metabolismo , Glándulas Suprarrenales/diagnóstico por imagen , Hiperplasia Suprarrenal Congénita/genética , Hiperplasia Suprarrenal Congénita/complicaciones , Hiperplasia Suprarrenal Congénita/patología , Hiperplasia Suprarrenal Congénita/metabolismoRESUMEN
Bilateral macronodular adrenocortical disease (BMAD) is an uncommon cause of Cushing's syndrome leading to bilateral macronodules. Isolated BMAD has been classified into three molecular groups: patients with ARMC5 alteration, KDM1A alteration, and patients without known genetic cause. The aim of this study was to identify by NGS, in a cohort of 26 patients with BMAD, the somatic alterations acquired in different nodules after macrodissection from patients with germline ARMC5 or KDM1A alterations and to analyze potential somatic alterations in a panel of five other genes involved in adrenal pathology (GNAS, PDE8B, PDE11A, PRKAR1A, and PRKACA). Twenty-three patients (7 ARMC5, 3 KDM1A, and 13 BMAD with unknown genetic cause) were analyzable. Somatic ARMC5 or KDM1A events were exclusively observed in patients with germline ARMC5 and KDM1A alterations, respectively. Six out of 7 ARMC5 patients have a high heterogeneity in identified somatic events, whereas one ARMC5 and all KDM1A patients show a loss of heterozygosity (LOH) in all nodules. Except for passenger alterations of GNAS, no genetic alteration susceptible to causing the disease was detected in the BMAD with unknown genetic cause. Our study reinforces our knowledge of the somatic genetic heterogeneity of ARMC5 and the somatic homogeneity of KDM1A. It reveals the absence of purely somatic events in these two genes and provides a new tool for detecting KDM1A alterations by FISH 1p36/1q25.
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Proteínas del Dominio Armadillo , Humanos , Masculino , Femenino , Persona de Mediana Edad , Adulto , Anciano , Proteínas del Dominio Armadillo/genética , Enfermedades de la Corteza Suprarrenal/genética , Enfermedades de la Corteza Suprarrenal/patología , Enfermedades de la Corteza Suprarrenal/complicaciones , Heterogeneidad Genética , Histona Demetilasas/genéticaRESUMEN
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.
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Movimiento Celular , Proliferación Celular , Regulación Neoplásica de la Expresión Génica , Histona Demetilasas , Proteínas de Membrana de los Lisosomas , Invasividad Neoplásica , Neovascularización Patológica , Neoplasias Pancreáticas , Humanos , Neoplasias Pancreáticas/patología , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo , Movimiento Celular/genética , Neovascularización Patológica/genética , Neovascularización Patológica/metabolismo , Histona Demetilasas/metabolismo , Histona Demetilasas/genética , Proliferación Celular/genética , Línea Celular Tumoral , Proteínas de Membrana de los Lisosomas/metabolismo , Proteínas de Membrana de los Lisosomas/genética , Angiogénesis , Proteínas de Neoplasias , Proteína 3 de la Membrana Asociada a LisosomaRESUMEN
Emerging preclinical autism research has shown the therapeutic promise of pharmacological inhibitors for epigenetic enzymes, such as histone deacetylases (HDAC), euchromatic histone methyltransferases (EHMT), and lysine-specific histone demethylase 1A (LSD1). These interventions restore gene expression, synaptic function, and behavioral performance in autism models, highlighting a new strategy for autism treatment.
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Trastorno Autístico , Epigénesis Genética , Histona Demetilasas , Humanos , Trastorno Autístico/tratamiento farmacológico , Trastorno Autístico/genética , Animales , Histona Demetilasas/antagonistas & inhibidores , Histona Demetilasas/metabolismo , Histona Demetilasas/genética , Inhibidores de Histona Desacetilasas/farmacología , Inhibidores de Histona Desacetilasas/uso terapéutico , N-Metiltransferasa de Histona-Lisina/antagonistas & inhibidores , N-Metiltransferasa de Histona-Lisina/genética , N-Metiltransferasa de Histona-Lisina/metabolismo , Histona Desacetilasas/metabolismo , Histona Desacetilasas/genéticaRESUMEN
The X and Y chromosomes play important roles outside of human reproduction; namely, their potential contribution to human sex biases in physiology and disease. While sex biases are often thought to be an effect of hormones and environmental exposures, genes encoded on the sex chromosomes also play a role. Seventeen homologous gene pairs exist on the X and Y chromosomes whose proteins have critical functions in biology, from direct regulation of transcription and translation to intercellular signaling and formation of extracellular structures. In this review, we cover the current understanding of several of these sex chromosome-encoded protein homologs that are involved in transcription and chromatin regulation: SRY/SOX3, ZFX/ZFY, KDM5C/KDM5D, UTX/UTY, and TBL1X/TBL1Y. Their mechanisms of gene regulation are discussed, including any redundancies or divergent roles of the X- and Y-chromosome homologs. Additionally, we discuss associated diseases related to these proteins and any sex biases that exist therein in an effort to drive further research into how these pairs contribute to sexually dimorphic gene regulation in health and disease.
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Regulación de la Expresión Génica , Humanos , Regulación de la Expresión Génica/genética , Animales , Histona Demetilasas/metabolismo , Histona Demetilasas/genética , Cromosomas Humanos Y/genética , Cromosomas Humanos X/genética , Caracteres Sexuales , Transducina/genética , Transducina/metabolismo , Cromosomas Sexuales/genética , Femenino , Proteínas Nucleares , Antígenos de Histocompatibilidad MenorRESUMEN
Functional and phenotypic heterogeneity of dendritic cells (DCs) play crucial roles in facilitating the development of diverse immune responses essential for host protection. Here, we report that KDM5C, a histone lysine demethylase, regulates conventional or classical DC (cDC) and plasmacytoid DC (pDC) population heterogeneity and function. Mice deficient in KDM5C in DCs have increased proportions of cDC2Bs and cDC1s, which is partly dependent on type I interferon (IFN) and pDCs. Loss of KDM5C results in an increase in Ly6C- pDCs, which, compared to Ly6C+ pDCs, have limited ability to produce type I IFN and more efficiently stimulate antigen-specific CD8 T cells. KDM5C-deficient DCs have increased expression of inflammatory genes, altered expression of lineage-specific genes, and decreased function. In response to Listeria infection, KDM5C-deficient mice mount reduced CD8 T cell responses due to decreased antigen presentation by cDC1s. Thus, KDM5C is a key regulator of DC heterogeneity and critical driver of the functional properties of DCs.
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Linfocitos T CD8-positivos , Células Dendríticas , Histona Demetilasas , Células Dendríticas/metabolismo , Células Dendríticas/inmunología , Animales , Ratones , Histona Demetilasas/metabolismo , Histona Demetilasas/genética , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , Ratones Endogámicos C57BL , Transcripción Genética , Interferón Tipo I/metabolismo , Presentación de AntígenoRESUMEN
Histone lysine demethylases (KDMs) play an essential role in biological processes such as transcription regulation, RNA maturation, transposable element control, and genome damage sensing and repair. In most cases, their action requires catalytic activities, but non-catalytic functions have also been shown in some KDMs. Indeed, some strictly KDM-related proteins and some KDM isoforms do not act as histone demethylase but show other enzymatic activities or relevant non-enzymatic functions in different cell types. Moreover, many studies have reported on functions potentially supported by catalytically dead mutant KDMs. This is probably due to the versatility of the catalytical core, which can adapt to assume different molecular functions, and to the complex multi-domain structure of these proteins which encompasses functional modules for targeting histone modifications, promoting protein-protein interactions, or recognizing nucleic acid structural motifs. This rich modularity and the availability of multiple isoforms in the various classes produced variants with enzymatic functions aside from histone demethylation or variants with non-catalytical functions during the evolution. In this review we will catalog the proteins with null or questionable demethylase activity and predicted or validated inactive isoforms, summarizing what is known about their alternative functions. We will then go through some experimental evidence for the non-catalytical functions of active KDMs.
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Histona Demetilasas , Histona Demetilasas/metabolismo , Histona Demetilasas/genética , Histona Demetilasas/química , Humanos , Animales , Histonas/metabolismoRESUMEN
Chronic hypoxia (CH) is commonly associated with various cardiovascular diseases, with cardiac hypertrophy being the most frequently observed alteration. Metabolic remodeling is another consequence seen in the hypoxic heart. However, the mechanistic linkage between metabolic remodeling and cardiac hypertrophy in the hypoxic heart remains unclear. In this study, wild-type C57BL/6J mice were subjected to CH for 4 wk. Echocardiography and morphological analysis were used to assess the cardiac effects. We found that 4 wk of CH led to significant cardiac hypertrophy in the mice, whereas cardiac function remained unchanged compared with normoxic mice. In addition, CH induced an elevation in cardiac alpha-ketoglutarate (α-KG) content. Promoting α-KG degradation in the CH hearts prevented CH-induced cardiac hypertrophy but led to noticeable cardiac dysfunction. Mechanistically, α-KG promoted the transcription of hypertrophy-related genes by regulating histone methylation. Silencing lysine-specific demethylase 5 (KDM5), a histone demethylation enzyme, blunted α-KG-induced transcription of hypertrophy-related genes. These data suggest that α-KG is required for CH-induced cardiac remodeling, thus establishing a connection between metabolic changes and cardiac remodeling in hypoxic hearts.NEW & NOTEWORTHY We reported that alpha-ketoglutarate (α-KG) is indispensable for chronic hypoxia (CH)-induced cardiac remodeling, which builds the bridge between metabolic intermediates and cardiac remodeling.
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Cardiomegalia , Hipoxia , Ácidos Cetoglutáricos , Ratones Endogámicos C57BL , Remodelación Ventricular , Animales , Ácidos Cetoglutáricos/metabolismo , Hipoxia/metabolismo , Remodelación Ventricular/efectos de los fármacos , Cardiomegalia/metabolismo , Cardiomegalia/patología , Cardiomegalia/fisiopatología , Cardiomegalia/genética , Ratones , Masculino , Enfermedad Crónica , Histona Demetilasas/metabolismo , Histona Demetilasas/genética , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/patologíaRESUMEN
Aim: This study investigates the altered expression and CpG methylation patterns of histone demethylase KDM8 in hepatocellular carcinoma (HCC), aiming to uncover insights and promising diagnostics biomarkers.Materials & methods: Leveraging TCGA-LIHC multi-omics data, we employed R/Bioconductor libraries and Cytoscape to analyze and construct a gene correlation network, and LASSO regression to develop an HCC-predictive model.Results: In HCC, KDM8 downregulation is correlated with CpGs hypermethylation. Differential gene correlation analysis unveiled a liver carcinoma-associated network marked by increased cell division and compromised liver-specific functions. The LASSO regression identified a highly accurate HCC prediction signature, prominently featuring CpG methylation at cg02871891.Conclusion: Our study uncovers CpG hypermethylation at cg02871891, possibly influencing KDM8 downregulation in HCC, suggesting these as promising biomarkers and targets.
Changes in gene function can play a role in causing cancer. In this study, we looked at how a specific gene called KDM8 behaves in liver cancer. By analyzing a large set of liver cancer samples, we investigated how gene interactions are different in this disease and if they can help predict liver cancer risk. Our results show that the KDM8 gene is less active, and its DNA gets chemically modified more often in liver cancer. We also found a group of genes and DNA changes, which are linked to the disease. Using this information, we identified 16 important markers and built a computer model that can accurately predict liver cancer. We found that DNA methylation at a specific spot called cg02871891 is especially important for predicting liver cancer. Overall, our study suggests that high levels of DNA methylation may lead to reduced KDM8 activity in liver cancer, which could be important for future research and better diagnostic tools.
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Carcinoma Hepatocelular , Islas de CpG , Metilación de ADN , Regulación Neoplásica de la Expresión Génica , Neoplasias Hepáticas , Aprendizaje Automático , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patología , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/metabolismo , Biomarcadores de Tumor/genética , Histona Demetilasas/genética , Histona Demetilasas/metabolismo , Redes Reguladoras de Genes , MultiómicaRESUMEN
BACKGROUND: DNMT3A is a crucial epigenetic regulation enzyme. However, due to its heterogeneous nature and frequent mutation in various cancers, the role of DNMT3A remains controversial. Here, we determine the role of DNMT3A in non-small cell lung cancer (NSCLC) to identify potential treatment strategies. METHODS: To investigate the role of loss-of-function mutations of DNMT3A in NSCLC, CRISPR/Cas9 was used to induce DNMT3A-inactivating mutations. Epigenetic inhibitor library was screened to find the synthetic lethal partner of DNMT3A. Both pharmacological inhibitors and gene manipulation were used to evaluate the synthetic lethal efficacy of DNMT3A/KDM1A in vitro and in vivo. Lastly, MS-PCR, ChIP-qPCR, dual luciferase reporter gene assay and clinical sample analysis were applied to elucidate the regulation mechanism of synthetic lethal interaction. RESULTS: We identified DNMT3A is a tumour suppressor gene in NSCLC and KDM1A as a synthetic lethal partner of DNMT3A deletion. Both chemical KDM1A inhibitors and gene manipulation can selectively reduce the viability of DNMT3A-KO cells through inducing cell apoptosis in vitro and in vivo. We clarified that the synthetic lethality is not only limited to the death mode, but also involved into tumour metastasis. Mechanistically, DNMT3A deficiency induces KDM1A upregulation through reducing the methylation status of the KDM1A promoter and analysis of clinical samples indicated that DNMT3A expression was negatively correlated with KDM1A level. CONCLUSION: Our results provide new insight into the role of DNMT3A in NSCLC and elucidate the mechanism of synthetic lethal interaction between KDM1A and DNMT3A, which might represent a promising approach for treating patients with DNMT3A-deficient tumours.
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Carcinoma de Pulmón de Células no Pequeñas , ADN (Citosina-5-)-Metiltransferasas , ADN Metiltransferasa 3A , Neoplasias Pulmonares , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/patología , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , Animales , Ratones , ADN (Citosina-5-)-Metiltransferasas/genética , ADN (Citosina-5-)-Metiltransferasas/antagonistas & inhibidores , Histona Demetilasas/genética , Histona Demetilasas/metabolismo , Histona Demetilasas/antagonistas & inhibidores , Línea Celular Tumoral , Apoptosis , Ensayos Antitumor por Modelo de Xenoinjerto , Regulación Neoplásica de la Expresión Génica , FemeninoRESUMEN
Quiescence, a hallmark of adult neural stem cells (NSCs), is required for maintaining the NSC pool to support life-long continuous neurogenesis in the adult dentate gyrus (DG). Whether long-lasting epigenetic modifications maintain NSC quiescence over the long term in the adult DG is not well-understood. Here we show that mice with haploinsufficiency of Setd1a, a schizophrenia risk gene encoding a histone H3K4 methyltransferase, develop an enlarged DG with more dentate granule cells after young adulthood. Deletion of Setd1a specifically in quiescent NSCs in the adult DG promotes their activation and neurogenesis, which is countered by inhibition of the histone demethylase LSD1. Mechanistically, RNA-sequencing and CUT & RUN analyses of cultured quiescent adult NSCs reveal Setd1a deletion-induced transcriptional changes and many Setd1a targets, among which down-regulation of Bhlhe40 promotes quiescent NSC activation in the adult DG in vivo. Together, our study reveals a Setd1a-dependent epigenetic mechanism that sustains NSC quiescence in the adult DG.