RESUMEN
The senescent microenvironment and aged cells per se contribute to tissue remodeling, chronic inflammation, and age-associated dysfunction. However, the metabolic and epigenomic bases of the senescence-associated secretory phenotype (SASP) remain largely unknown. Here, we show that ATP-citrate lyase (ACLY), a key enzyme in acetyl-coenzyme A (CoA) synthesis, is essential for the pro-inflammatory SASP, independent of persistent growth arrest in senescent cells. Citrate-derived acetyl-CoA facilitates the action of SASP gene enhancers. ACLY-dependent de novo enhancers augment the recruitment of the chromatin reader BRD4, which causes SASP activation. Consistently, specific inhibitions of the ACLY-BRD4 axis suppress the STAT1-mediated interferon response, creating the pro-inflammatory microenvironment in senescent cells and tissues. Our results demonstrate that ACLY-dependent citrate metabolism represents a selective target for controlling SASP designed to promote healthy aging.
Asunto(s)
ATP Citrato (pro-S)-Liasa , Senescencia Celular , Ácido Cítrico , Factores de Transcripción , Animales , Humanos , ATP Citrato (pro-S)-Liasa/metabolismo , ATP Citrato (pro-S)-Liasa/genética , Ácido Cítrico/metabolismo , Factores de Transcripción/metabolismo , Ratones , Inflamación/metabolismo , Inflamación/patología , Microambiente Celular , Acetilcoenzima A/metabolismo , Elementos de Facilitación Genéticos/genética , Ratones Endogámicos C57BL , Proteínas Nucleares/metabolismoRESUMEN
Skeletal muscle exhibits remarkable plasticity in response to environmental cues, with stress-dependent effects on the fast-twitch and slow-twitch fibers. Although stress-induced gene expression underlies environmental adaptation, it is unclear how transcriptional and epigenetic factors regulate fiber type-specific responses in the muscle. Here, we show that flavin-dependent lysine-specific demethylase-1 (LSD1) differentially controls responses to glucocorticoid and exercise in postnatal skeletal muscle. Using skeletal muscle-specific LSD1-knockout mice and in vitro approaches, we found that LSD1 loss exacerbated glucocorticoid-induced atrophy in the fast fiber-dominant muscles, with reduced nuclear retention of Foxk1, an anti-autophagic transcription factor. Furthermore, LSD1 depletion enhanced endurance exercise-induced hypertrophy in the slow fiber-dominant muscles, by induced expression of ERRγ, a transcription factor that promotes oxidative metabolism genes. Thus, LSD1 serves as an 'epigenetic barrier' that optimizes fiber type-specific responses and muscle mass under the stress conditions. Our results uncover that LSD1 modulators provide emerging therapeutic and preventive strategies against stress-induced myopathies such as sarcopenia, cachexia, and disuse atrophy.
Asunto(s)
Glucocorticoides , Enfermedades Musculares , Ratones , Animales , Glucocorticoides/metabolismo , Músculo Esquelético/metabolismo , Fibras Musculares Esqueléticas/metabolismo , Factores de Transcripción/metabolismo , Histona Demetilasas/genética , Histona Demetilasas/metabolismoRESUMEN
Mechanisms of dipeptidyl peptidase-4 inhibitors, glucagon-like peptide-1 receptor agonists and glucagon-like peptide-1 receptor/glucose-dependent insulinotropic polypeptide receptor dual-agonist in glycemic control and/or weight loss.
Asunto(s)
Diabetes Mellitus Tipo 2 , Inhibidores de la Dipeptidil-Peptidasa IV , Humanos , Incretinas/uso terapéutico , Incretinas/farmacología , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Hipoglucemiantes/uso terapéutico , Hipoglucemiantes/farmacología , Receptor del Péptido 1 Similar al Glucagón/agonistas , Inhibidores de la Dipeptidil-Peptidasa IV/uso terapéutico , Inhibidores de la Dipeptidil-Peptidasa IV/farmacologíaRESUMEN
The high glycolytic activity of cancer cells leads to lactic acidosis (LA) in the tumor microenvironment. LA is not merely a consequence of metabolic activities but also has functional roles in metabolic reprogramming and cancer progression. Cholangiocarcinoma (CCA) cells exhibit a high dependency on glycolysis for survival and growth, but the specific effects of LA on cellular characteristics remain unknown. Here, we demonstrate that long-term LA (LLA) reprograms the metabolic phenotype of CCA cells from glycolytic to oxidative and enhances their migratory activity. In CCA cell culture, short-term LA (24 h) showed a growth inhibitory effect, while extended LA exposure for more than 2 weeks (LLA) led to enhanced cell motility. Coincidentally, LLA enhanced the respiratory capacity with an increase in mitochondrial mass. Inhibition of mitochondrial function abolished LLA-induced cell motility, suggesting that metabolic remodeling affects the phenotypic outcomes. RNA-sequencing analysis revealed that LLA upregulated genes associated with cell migration and epithelial-mesenchymal transition (EMT), including thrombospondin-1 (THBS1), which encodes a pro-EMT-secreted protein. Inhibition of THBS1 resulted in the suppression of both LLA-induced cell motility and respiratory capacity. Moreover, high THBS1 expression was associated with poor survival in patients with CCA. Collectively, our study suggests that the increased expression of THBS1 by LLA promotes phenotypic alterations, leading to CCA progression.
Asunto(s)
Acidosis Láctica , Neoplasias de los Conductos Biliares , Colangiocarcinoma , Humanos , Regulación hacia Arriba , Acidosis Láctica/genética , Línea Celular Tumoral , Colangiocarcinoma/patología , Transición Epitelial-Mesenquimal/genética , Fenotipo , Movimiento Celular/genética , Conductos Biliares Intrahepáticos/metabolismo , Neoplasias de los Conductos Biliares/patología , Trombospondinas/genética , Microambiente Tumoral/genéticaRESUMEN
Acute myeloid leukemia (AML) is a heterogenous malignancy characterized by distinct lineage subtypes and various genetic/epigenetic alterations. As with other neoplasms, AML cells have well-known aerobic glycolysis, but metabolic variations depending on cellular lineages also exist. Lysine-specific demethylase-1 (LSD1) has been reported to be crucial for human leukemogenesis, which is currently one of the emerging therapeutic targets. However, metabolic roles of LSD1 and lineage-dependent factors remain to be elucidated in AML cells. Here, we show that LSD1 directs a hematopoietic lineage-specific metabolic program in AML subtypes. Erythroid leukemia (EL) cells particularly showed activated glycolysis and high expression of LSD1 in both AML cell lines and clinical samples. Transcriptome, chromatin immunoprecipitation-sequencing, and metabolomic analyses revealed that LSD1 was essential not only for glycolysis but also for heme synthesis, the most characteristic metabolic pathway of erythroid origin. Notably, LSD1 stabilized the erythroid transcription factor GATA1, which directly enhanced the expression of glycolysis and heme synthesis genes. In contrast, LSD1 epigenetically downregulated the granulo-monocytic transcription factor C/EBPα. Thus, the use of LSD1 knockdown or chemical inhibitor dominated C/EBPα instead of GATA1 in EL cells, resulting in metabolic shifts and growth arrest. Furthermore, GATA1 suppressed the gene encoding C/EBPα that then acted as a repressor of GATA1 target genes. Collectively, we conclude that LSD1 shapes metabolic phenotypes in EL cells by balancing these lineage-specific transcription factors and that LSD1 inhibitors pharmacologically cause lineage-dependent metabolic remodeling.
Asunto(s)
Leucemia Eritroblástica Aguda , Proteína alfa Potenciadora de Unión a CCAAT , Factor de Transcripción GATA1/genética , Histona Demetilasas/genética , Humanos , Leucemia Eritroblástica Aguda/genética , Proteínas Proto-Oncogénicas , Factores de TranscripciónRESUMEN
Various nutritional signals are transduced by two epigenetic pathways: NAD-dependent sirtuin Sirt1 (NAD+-Sirt1) deacetylase and flavin adenine dinucleotide-dependent lysine-specific demethylase 1 (FAD-LSD1). These pathways are controlled by dietary vitamins and nutrient-responsive hormones such as glucocorticoids and insulin, resulting in endocrine-metabolism-epigenome cooperation in adipocyte and skeletal muscle development.
Asunto(s)
Flavina-Adenina Dinucleótido/metabolismo , Histona Demetilasas/metabolismo , NAD/metabolismo , Sirtuina 1/metabolismo , Adipocitos/citología , Adipocitos/metabolismo , Animales , Flavina-Adenina Dinucleótido/genética , Glucocorticoides/metabolismo , Histona Demetilasas/genética , Humanos , NAD/genética , Transducción de Señal/genética , Transducción de Señal/fisiología , Sirtuina 1/genéticaRESUMEN
Transcriptional and epigenetic regulation is fundamentally involved in initiating and maintaining progression of cellular differentiation. The 2 types of thermogenic adipocytes, brown and beige, are thought to be of different origins but share functionally similar phenotypes. Here, we report that lysine-specific demethylase 2 (LSD2) regulates the expression of genes associated with lineage identity during the differentiation of brown and beige adipogenic progenitors in mice. In HB2 mouse brown preadipocytes, short hairpin RNA-mediated knockdown (KD) of LSD2 impaired formation of lipid droplet-containing adipocytes and down-regulated brown adipogenesis-associated genes. Transcriptomic analysis revealed that myogenesis-associated genes were up-regulated in LSD2-KD cells under adipogenic induction. In addition, loss of LSD2 during later phases of differentiation had no obvious influence on adipogenic traits, suggesting that LSD2 functions during earlier phases of brown adipocyte differentiation. Using adipogenic cells from the brown adipose tissues of LSD2-knockout (KO) mice, we found reduced expression of brown adipogenesis genes, whereas myogenesis genes were not affected. In contrast, when LSD2-KO cells from inguinal white adipose tissues were subjected to beige induction, these cells showed a dramatic rise in myogenic gene expression. Collectively, these results suggest that LSD2 regulates distinct sets of genes during brown and beige adipocyte formation.-Takase, R., Hino, S., Nagaoka, K., Anan, K., Kohrogi, K., Araki, H., Hino, Y., Sakamoto, A., Nicholson, T. B., Chen, T., Nakao, M. Lysine-specific demethylase-2 is distinctively involved in brown and beige adipogenic differentiation.
Asunto(s)
Tejido Adiposo Pardo/citología , Tejido Adiposo Pardo/metabolismo , Histona Demetilasas/metabolismo , ARN Interferente Pequeño/metabolismo , Adipogénesis/genética , Adipogénesis/fisiología , Animales , Western Blotting , Diferenciación Celular/genética , Diferenciación Celular/fisiología , Células Cultivadas , Inmunoprecipitación de Cromatina , Femenino , Histona Demetilasas/genética , Lentivirus/genética , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , PPAR gamma/metabolismo , ARN Interferente Pequeño/genética , Reacción en Cadena en Tiempo Real de la PolimerasaRESUMEN
AIMS/INTRODUCTION: Gestational diabetes mellitus (GDM) is a risk for adverse perinatal outcomes, and patients with a history of GDM have an increased risk of impaired glucose tolerance (IGT). Here, we carried out two non-interventional and retrospective studies of GDM patients in Japan. MATERIALS AND METHODS: In the first study, we enrolled 529 GDM patients and assessed predictors of the need for insulin therapy. In the second study, we enrolled 185 patients from the first study, and assessed predictors of postpartum IGT. RESULTS: In the first study, gestational weeks at GDM diagnosis and history of pregnancy were significantly lower, and pregestational body mass index, family history of diabetes mellitus, 1- and 2-h glucose levels in a 75-g oral glucose tolerance test (OGTT), the number of abnormal values in a 75-g OGTT, and glycated hemoglobin were significantly higher in participants receiving insulin therapy. In the second study, 1- and 2-h glucose levels in a 75-g OGTT, the number of abnormal values in a 75-g OGTT, glycated hemoglobin, and ketone bodies in a urine test were significantly higher in participants with OGT. Logistic regression analysis showed that gestational weeks at GDM diagnosis, 1-h glucose levels in a 75-g OGTT and glycated hemoglobin were significant predictors of the need for insulin therapy, and 1-h glucose levels in a 75-g OGTT at diagnosis and ketone bodies in a urine test were significant predictors for postpartum IGT. CONCLUSIONS: Antepartum 1-h glucose levels in a 75-g OGTT was a predictor of the need for insulin therapy in pregnancy and postpartum IGT.
Asunto(s)
Diabetes Gestacional/diagnóstico , Diabetes Gestacional/tratamiento farmacológico , Intolerancia a la Glucosa/diagnóstico , Intolerancia a la Glucosa/tratamiento farmacológico , Prueba de Tolerancia a la Glucosa/métodos , Hipoglucemiantes/uso terapéutico , Insulina/uso terapéutico , Adulto , Glucemia/análisis , Femenino , Edad Gestacional , Intolerancia a la Glucosa/complicaciones , Humanos , Japón , Periodo Posparto , Embarazo , Estudios Retrospectivos , Factores de RiesgoRESUMEN
The metabolic properties of cells are formed under the influence of environmental factors such as nutrients and hormones. Although such a metabolic program is likely initiated through epigenetic mechanisms, the direct links between metabolic cues and activities of chromatin modifiers remain largely unknown. In this study, we show that lysine-specific demethylase-1 (LSD1) controls the metabolic program in myogenic differentiation, under the action of catabolic hormone, glucocorticoids. By using transcriptomic and epigenomic approaches, we revealed that LSD1 bound to oxidative metabolism and slow-twitch myosin genes, and repressed their expression. Consistent with this, loss of LSD1 activity during differentiation enhanced the oxidative capacity of myotubes. By testing the effects of various hormones, we found that LSD1 levels were decreased by treatment with the glucocorticoid dexamethasone (Dex) in cultured myoblasts and in skeletal muscle from mice. Mechanistically, glucocorticoid signaling induced expression of a ubiquitin E3 ligase, JADE-2, which was responsible for proteasomal degradation of LSD1. Consequently, in differentiating myoblasts, chemical inhibition of LSD1, in combination with Dex treatment, synergistically de-repressed oxidative metabolism genes, concomitant with increased histone H3 lysine 4 methylation at these loci. These findings demonstrated that LSD1 serves as an epigenetic regulator linking glucocorticoid action to metabolic programming during myogenic differentiation.
Asunto(s)
Dexametasona/farmacología , Glucocorticoides/farmacología , Histona Demetilasas/metabolismo , Desarrollo de Músculos/genética , Fibras Musculares Esqueléticas/metabolismo , Músculo Esquelético/citología , Animales , Diferenciación Celular/genética , Línea Celular Tumoral , Histona Demetilasas/antagonistas & inhibidores , Histonas/metabolismo , Masculino , Metilación , Ratones , Ratones Endogámicos C57BL , Músculo Esquelético/metabolismo , Oxidación-Reducción , Ubiquitina-Proteína Ligasas/metabolismoRESUMEN
BACKGROUND: Pseudosarcomatous fibromyxoid tumor (PFT) of the urinary bladder is an uncommon benign lesion that can involve any site in the bladder. Cellular features of PFT of the bladder are exceedingly rare. We describe the urinary cytology in a PFT patient who displayed numerous papillary fragments that suggested a malignant tumor. CASE: A 52-year-old man was seen at the hospital for evaluation of gross hematuria. At cystoscopy, the urologist observed a 3-cm, smooth, polypoid and ulcerated mass extending from the trigone to the bladder neck. Urinary cytology showed many papillary clusters with irregular nuclear margins in the bloody cell background. No spindle cells were noted. Cytology was interpreted as papillary growth, factor transitional cell carcinoma, grade 2-3. A laparotomy with partial resection of the urinary bladder was carried out, and histologically the tumor was composed of spindle, stellate, fibroblastic cells embedded in myxoid stroma with little collagen. Immunohistochemical and ultrastructural studies revealed the fibroblastic nature of the lesion. The final diagnosis was PFT of the bladder on the basis of histologic examination of the resected material. CONCLUSION: Papillary fragments are a diagnostic pitfall in urinary cytology of PFT lesions.
Asunto(s)
Errores Diagnósticos/prevención & control , Fibroblastos/patología , Fibroma/patología , Neoplasias de la Vejiga Urinaria/patología , Vejiga Urinaria/patología , Biomarcadores de Tumor/metabolismo , Carcinoma de Células Transicionales/patología , Carcinoma de Células Transicionales/orina , Diagnóstico Diferencial , Retículo Endoplásmico/patología , Retículo Endoplásmico/ultraestructura , Fibroblastos/metabolismo , Fibroblastos/ultraestructura , Fibroma/orina , Hematuria/etiología , Hematuria/patología , Humanos , Inmunohistoquímica , Queratinas/metabolismo , Masculino , Microscopía Electrónica , Persona de Mediana Edad , Vejiga Urinaria/ultraestructura , Neoplasias de la Vejiga Urinaria/orina , Orina/citología , Vimentina/metabolismoRESUMEN
A 52-year-old man presented with gross hematuria. He had neither history of urinary tract infection nor trauma. Cystoscopy revealed a bladder tumor with ulcer on a left lateral wall. Computed tomography confirmed a round solid mass 3 cm in diameter invading deeply into the muscle layer of the urinary bladder. Transurethral biopsy revealed an inflammatory pseudotumor of the urinary bladder. Partial cystectomy was performed. This is the 38th reported case of inflammatory pseudotumor of the urinary bladder in Japan. No local recurrence was seen 3 months after surgery.
Asunto(s)
Granuloma de Células Plasmáticas/cirugía , Enfermedades de la Vejiga Urinaria/cirugía , Cistectomía , Cistoscopía , Granuloma de Células Plasmáticas/patología , Humanos , Masculino , Persona de Mediana Edad , Enfermedades de la Vejiga Urinaria/patologíaRESUMEN
BACKGROUND: The present study was designed to ascertain retrospectively the validity of ursodeoxycholic acid (UDCA) in the treatment of prostate cancer in terms of prophylactic effects on the occurrence of flutamide-induced hepatopathy in a large number of patients surveyed in a multi-center cooperative study. METHODS: One hundred and eighty-one patients (74.1 +/- 4.9 years) with prostate cancer treated with flutamide with (n = 70) or without (n = 111) UDCA were retrospectively evaluated and the occurrence of hepatopathy was compared between these two patient groups. RESULTS: Between patients treated with UDCA and those without it, no significant differences were noted in age, clinical stage, grade, duration of flutamide administration and serum prostate-specific antigen (PSA) levels before treatment. However, there were significant differences in the presence or absence of previous treatments and treatments used together with flutamide. The incidence of hepatopathy was 11.4% (8/70) in patients with UDCA and 32.4% (36/111) in those without it, showing a statistically significant difference (P < 0.05). The hepatopathy-free rate obtained by the Kaplan-Meier method was also significantly higher in patients with UDCA (88.4% 1 year following flutamide administration) than that in those without it (59.6%) (P < 0.005). CONCLUSION: These results suggest that UDCA has a prophylactic effect against flutamide-induced hepatopathy in patients with prostate cancer.