RESUMEN
Janus tyrosine kinase 2 (JAK2)-signal transducer and activator of transcription 3 (STAT3) signaling pathway is essential for modulating cellular development, differentiation, and homeostasis. Thus, dysregulation of JAK2-STAT3 signaling pathway is frequently associated with human malignancies. Here, we provide evidence that lysine-specific demethylase 3A (KDM3A) functions as an essential epigenetic enzyme for the activation of JAK2-STAT3 signaling pathway. KDM3A is tyrosine-phosphorylated by JAK2 in the nucleus and functions as a STAT3-dependent transcriptional coactivator. JAK2-KDM3A signaling cascade induced by IL-6 leads to alteration of histone H3K9 methylation as a predominant epigenetic event, thereby providing the functional and mechanistic link between activation of JAK2-STAT3 signaling pathway and its epigenetic control. Together, our findings demonstrate that inhibition of KDM3A phosphorylation could be a potent therapeutic strategy to control oncogenic effect of JAK2-STAT3 signaling pathway.
Asunto(s)
Histona Demetilasas con Dominio de Jumonji/metabolismo , Epigénesis Genética , Células HEK293/metabolismo , Células HeLa , Histonas/metabolismo , Humanos , Interleucina-6/metabolismo , Janus Quinasa 2/metabolismo , Histona Demetilasas con Dominio de Jumonji/genética , Fosforilación , Proteínas Tirosina Quinasas/metabolismo , Factor de Transcripción STAT3/metabolismo , Transducción de Señal , Activación TranscripcionalRESUMEN
Autophagy is an essential process to maintain cell survival and homeostasis under various stress conditions. Here, we report that lysine-specific demethylase 3A (KDM3A) plays an important role in starvation-induced autophagy. Using Kdm3a knockout mice, we demonstrate that KDM3A is crucial for proper hepatic autophagy in vivo. Hepatic mRNA expression analysis and ChIP assay in WT and Kdm3a knockout mouse livers reveal that KDM3A activates autophagy genes by reducing histone H3K9me2 levels upon fasting. Together, our finding represents previously unidentified function of KDM3A as a key regulator of autophagy, implicating potential therapeutic approaches for autophagy-related diseases.
Asunto(s)
Autofagia , Histona Demetilasas con Dominio de Jumonji/metabolismo , Animales , Autofagosomas/metabolismo , Ayuno , Fibroblastos/metabolismo , Regulación de la Expresión Génica , Células Hep G2 , Humanos , Histona Demetilasas con Dominio de Jumonji/genética , Hígado/citología , Hígado/metabolismo , Lisosomas/metabolismo , Masculino , Ratones Endogámicos C57BL , Ratones Noqueados , ARN Mensajero/genética , ARN Mensajero/metabolismoRESUMEN
Ubiquitination plays a major role in protein degradation. Although phosphorylation-dependent ubiquitination is well known for the regulation of protein stability, methylation-dependent ubiquitination machinery has not been characterized. Here, we provide evidence that methylation-dependent ubiquitination is carried out by damage-specific DNA binding protein 1 (DDB1)/cullin4 (CUL4) E3 ubiquitin ligase complex and a DDB1-CUL4-associated factor 1 (DCAF1) adaptor, which recognizes monomethylated substrates. Molecular modeling and binding affinity studies reveal that the putative chromo domain of DCAF1 directly recognizes monomethylated substrates, whereas critical binding pocket mutations of the DCAF1 chromo domain ablated the binding from the monomethylated substrates. Further, we discovered that enhancer of zeste homolog 2 (EZH2) methyltransferase has distinct substrate specificities for histone H3K27 and nonhistones exemplified by an orphan nuclear receptor, RORα. We propose that EZH2-DCAF1/DDB1/CUL4 represents a previously unrecognized methylation-dependent ubiquitination machinery specifically recognizing "methyl degron"; through this, nonhistone protein stability can be dynamically regulated in a methylation-dependent manner.
Asunto(s)
Proteínas Portadoras/metabolismo , Proteínas Cullin/metabolismo , Proteínas de Unión al ADN/metabolismo , Complejo Represivo Polycomb 2/metabolismo , Ubiquitina-Proteína Ligasas/metabolismo , Proteína Potenciadora del Homólogo Zeste 2 , Humanos , Células MCF-7 , Metilación , Miembro 1 del Grupo F de la Subfamilia 1 de Receptores Nucleares/metabolismo , Proteínas Serina-Treonina Quinasas , Especificidad por SustratoRESUMEN
The actions of transcription factors, chromatin modifiers and noncoding RNAs are crucial for the programming of cell states. Although the importance of various epigenetic machineries for controlling pluripotency of embryonic stem (ES) cells has been previously studied, how chromatin modifiers cooperate with specific transcription factors still remains largely elusive. Here, we find that Pontin chromatin remodelling factor plays an essential role as a coactivator for Oct4 for maintenance of pluripotency in mouse ES cells. Genome-wide analyses reveal that Pontin and Oct4 share a substantial set of target genes involved in ES cell maintenance. Intriguingly, we find that the Oct4-dependent coactivator function of Pontin extends to the transcription of large intergenic noncoding RNAs (lincRNAs) and in particular linc1253, a lineage programme repressing lincRNA, is a Pontin-dependent Oct4 target lincRNA. Together, our findings demonstrate that the Oct4-Pontin module plays critical roles in the regulation of genes involved in ES cell fate determination.
Asunto(s)
ADN Helicasas/genética , Epigénesis Genética , Células Madre Embrionarias de Ratones/metabolismo , Factor 3 de Transcripción de Unión a Octámeros/genética , ARN Largo no Codificante/genética , Animales , Diferenciación Celular , Cromatina/química , Cromatina/metabolismo , Ensamble y Desensamble de Cromatina , ADN Helicasas/deficiencia , Perfilación de la Expresión Génica , Estudio de Asociación del Genoma Completo , Ratones , Ratones Noqueados , Células Madre Embrionarias de Ratones/citología , Factor 3 de Transcripción de Unión a Octámeros/deficiencia , Receptores Patched , Células Madre Pluripotentes/citología , Células Madre Pluripotentes/metabolismo , ARN Largo no Codificante/metabolismo , Receptores de Superficie Celular/genética , Receptores de Superficie Celular/metabolismo , Transducción de Señal , Proteínas de Unión a Telómeros/genética , Proteínas de Unión a Telómeros/metabolismo , Inhibidor Tisular de Metaloproteinasa-2/genética , Inhibidor Tisular de Metaloproteinasa-2/metabolismo , Tropomiosina/genética , Tropomiosina/metabolismoRESUMEN
OBJECTIVE: To analyze cases of ovarian leiomyomas and to discuss the proper surgical management. DESIGN: A case series and discussion. SETTING: General university hospital and healthcare center. PATIENT(S): Nine patients who were diagnosed with ovarian leiomyomas after surgery between 1993 and 2009. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): A preoperative diagnosis that was matched to the postoperative diagnosis and the type of surgery. RESULT(S): In all cases, ovarian leiomyoma was misdiagnosed preoperatively as pedunculated uterine myoma, ovarian fibroma, or even ovarian endometrioma. Seven (77.8%) of the nine patients underwent a salpingo-oophorectomy or an oophorectomy with or without hysterectomy, and only two (22.2%) patients were submitted to an ovary-preserving surgery (i.e., a cystectomy or ovarian wedge resection). CONCLUSION(S): Because of their extreme rarity, ovarian leiomyomas are seldom suspected intraoperatively or preoperatively. However, most of these tumors appear at reproductive age and have a benign nature, similar to uterine myomas. Therefore, surgeons should perform ovary-preserving management, especially in young patients.