RESUMEN
Melanoma belongs to cutaneous malignancy. Long non-coding RNAs (lncRNAs) have been suggested as crucial effectors in modulating progression of different malignancies, including melanoma. However, novel lncRNA solute carrier organic anion transporter family member 4A1 antisense RNA 1 (SLCO4A1-AS1) was not reported in melanoma. Herein, SLCO4A1-AS1 was detected to be up-regulated in melanoma cell lines compared with human normal melanocytes (HEM-a). Additionally, proliferation, migration and invasion of melanoma cells were weakened but apoptosis was facilitated due to SLCO4A1-AS1 down-regulation. Subsequently, miR-1306-5p was revealed to be sequestered by SLCO4A1-AS1 and down-regulated in melanoma cells. Functional assays further sustained that overexpressed miR-1306-5p had inhibitory influence on proliferation, migration and invasion and promoting influence on apoptosis of melanoma cells. Polycomb group ring finger 2 (PCGF2) was predicted as the downstream of miR-1306-5p, displaying aberrantly high expression in melanoma cell lines. Furthermore, PCGF2 expression was negatively modulated by miR-1306-5p and positively regulated by SLCO4A1-AS1. Finally, rescue assays demonstrated melanoma cell malignant behaviours suppressed by SLCO4A1-AS1 knockdown could be reversed by overexpressed PCGF2. Our study suggested that SLCO4A1-AS1 promoted the melanoma cell malignant behaviours via targeting miR-1306-5p/PCGF2, which might facilitate the discovery of novel biomarkers for melanoma treatment.
Asunto(s)
Melanoma , MicroARNs , ARN Largo no Codificante , Línea Celular Tumoral , Movimiento Celular/genética , Proliferación Celular/genética , Regulación Neoplásica de la Expresión Génica , Humanos , Melanoma/genética , MicroARNs/genética , MicroARNs/metabolismo , Complejo Represivo Polycomb 1 , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismoRESUMEN
Turnpenny-Fry syndrome is a very rare genetic disorder characterized by intellectual disability, developmental delay, facial dysmorphism, and skeletal abnormalities. Mutations of the PCGF2 gene are responsible for Turnpenny-Fry syndrome. This gene encodes the polycomb group ring finger 2 protein that is broadly expressed in various human tissues. To date, only 13 patients with Turnpenny-Fry syndrome have been reported. Our patient was referred to our clinic for neuromotor retardation and dysmorphic features. Whole exome sequencing (WES) was performed from the peripheral blood sample of the patient. WES revealed a heterozygous mutation in the PCGF2 gene. To the best of our knowledge, we reported the 14th patient with Turnpenny-Fry syndrome and the first from Turkey, who had new findings.
Asunto(s)
Discapacidad Intelectual , Anomalías Musculoesqueléticas , Humanos , Discapacidad Intelectual/diagnóstico , Discapacidad Intelectual/genética , Mutación , Turquía , Secuenciación del ExomaRESUMEN
PCGF2 encodes the polycomb group ring finger 2 protein, a transcriptional repressor involved in cell proliferation, differentiation, and embryogenesis. PCGF2 is a component of the polycomb repressive complex 1 (PRC1), a multiprotein complex which controls gene silencing through histone modification and chromatin remodelling. We report the phenotypic characterization of 13 patients (11 unrelated individuals and a pair of monozygotic twins) with missense mutations in PCGF2. All the mutations affected the same highly conserved proline in PCGF2 and were de novo, excepting maternal mosaicism in one. The patients demonstrated a recognizable facial gestalt, intellectual disability, feeding problems, impaired growth, and a range of brain, cardiovascular, and skeletal abnormalities. Computer structural modeling suggests the substitutions alter an N-terminal loop of PCGF2 critical for histone biding. Mutant PCGF2 may have dominant-negative effects, sequestering PRC1 components into complexes that lack the ability to interact efficiently with histones. These findings demonstrate the important role of PCGF2 in human development and confirm that heterozygous substitutions of the Pro65 residue of PCGF2 cause a recognizable syndrome characterized by distinctive craniofacial, neurological, cardiovascular, and skeletal features.
RESUMEN
Arsenic trioxide (ATO) is a therapeutic agent for acute promyelocytic leukemia (APL) which induces PML-RARA protein degradation via enhanced UBE2I-mediated sumoylation. PCGF2, a Polycomb group protein, has been suggested as an anti-SUMO E3 protein by inhibiting the sumoylation of UBE2I substrates, HSF2 and RANGAP1, via direct interaction. Thus, we hypothesized that PCGF2 might play a role in ATO-induced PML-RARA degradation by interacting with UBE2I. PCGF2 protein was down-regulated upon ATO treatment in human APL cell line, NB4. Knockdown of PCGF2 in NB4 cells, in the absence of ATO treatment, was sufficient to induce sumoylation-, ubiquitylation- and PML nuclear body-mediated degradation of PML-RARA protein. Moreover, overexpression of PCGF2 protected ATO-mediated degradation of ectopic and endogenous PML-RARA in 293T and NB4 cells, respectively. In 293T cells, UBE2I-mediated PML-RARA degradation was reduced upon PCGF2 co-expression. In addition, UBE2I-mediated sumoylation of PML-RARA was reduced upon PCGF2 co-expression and PCGF2-UBE2I interaction was confirmed by co-immunoprecipitation. Likewise, endogenous PCGF2-UBE2I interaction was detected by co-immunoprecipitation and immunofluorescence assays in NB4 cells. Intriguingly, upon ATO-treatment, such interaction was disrupted and UBE2I was co-immunoprecipitated or co-localized with its SUMO substrate, PML-RARA. Taken together, our results suggested a novel role of PCGF2 in ATO-mediated degradation of PML-RARA that PCGF2 might act as a negative regulator of UBE2I via direct interaction.
Asunto(s)
Antineoplásicos/farmacología , Arsenicales/farmacología , Leucemia Promielocítica Aguda/tratamiento farmacológico , Proteínas de Fusión Oncogénica/metabolismo , Óxidos/farmacología , Complejo Represivo Polycomb 1/metabolismo , Enzimas Ubiquitina-Conjugadoras/metabolismo , Trióxido de Arsénico , Línea Celular Tumoral , Técnica del Anticuerpo Fluorescente , Regulación Enzimológica de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Células HEK293 , Humanos , Inmunoprecipitación , Leucemia Promielocítica Aguda/enzimología , Leucemia Promielocítica Aguda/genética , Leucemia Promielocítica Aguda/patología , Proteínas de Fusión Oncogénica/genética , Complejo Represivo Polycomb 1/genética , Unión Proteica , Proteolisis , Interferencia de ARN , Transducción de Señal/efectos de los fármacos , Sumoilación , Factores de Tiempo , Transfección , Enzimas Ubiquitina-Conjugadoras/genética , UbiquitinaciónRESUMEN
Turnpenny-Fry Syndrome (TPFS) is a rare genetic disorder characterized by a severe developmental delay and a distinctive facial gestalt. It is caused by mutations in the Polycomb Group Ring Finger Protein 2 (PCGF2) gene, which is also known to play a role in numerous tumor types. Up to date, there have been no published case reports of patients with TPFS and concomitant malignancies. The present case describes the clinical evaluation and follow-up of a male infant with severe global developmental delay (GDD) and a distinctive phenotype. At 4 years of age, clinical exome sequencing confirmed the diagnosis of TPFS. Posteriorly, at 5 years of age, the patient was also diagnosed with T-cell acute lymphoblastic leukemia (ALL). Given the scarce literature regarding this syndrome, the authors expect that this case report will provide valuable information that could improve the follow-up of patients with TPFS. Furthermore, this case highlights the necessity for the appropriate diagnosis of developmental disorders, to ensure adequate care, surveillance of comorbidities and proper genetic counselling.
RESUMEN
Ovarian follicles are the fundamental structure to support oocyte development, which provides mature oocytes for offspring. This process requires granulosa cells (GCs) to respond to the midcycle surge of hormones, leading to GC proliferation and differentiation by a series of genes' transcriptional expression changes. Epigenetic mediator, Polycomb Repressive Complex 1 (PRC1) has been reported to function in fetal ovarian development. However, its functional relevance to folliculogenesis and ovulation remains unknown. In this study, we demonstrated that GC-selective depletion of PCGF2, a key component of PRC1, led to the loss of follicles, ovulation defects, and a lengthened estrus cycle, resulting in subfertility in female mice. The expression of PCGF2 is in the GCs of growing follicles and increases after human chorionic gonadotropin (hCG) stimulation. PCGF2 bound to the promoter of the key ovulation gene progesterone receptor (Pgr) and upregulated the expression of Pgr by targeting the epigenetic modification of H2AK119ub1 after hCG surge. Consistently, the expression of downstream genes of Pgr also sharply decreased, which resulted in the follicular rupture failed and oocyte entrapped in corpus luteum in GC-specific Pcgf2 knockout mice. Together, our study identified that PCGF2 is essential for folliculogenesis and ovulation via modulating hormone receptor expression.
RESUMEN
BACKGROUND: Turnpenny-Fry syndrome (TPFS) has recently been defined as an uncommon monogenic disease and is characterized by global developmental delay (GDD), intellectualdisability (ID), facial dysmorphology, and skeletal abnormality. PCGF2 is the only known causative gene for TPFS, which is a component of polycomb repressive complex 1 (PRC1). PRC1 is a multi-protein complex controlling the knockdown of gene expression. METHODS: The present study included the clinical evaluation of a 2.5-year-old boy with GDD and ID using cerebral MRI and the genetic testing with whole-exome sequencing. Additionally, the in silico molecular dynamic (MD) simulation was carried out on the identified variant. RESULTS: A recurrent missense variant, namely PCGF2: c.194C > T (p.Pro65Leu), was identified and suggested to be inherited from a mosaic father based on Sanger sequencing validation. MD results suggested a deleterious effect on the intramolecular structural flexibility and stability of PCGF2 protein by this variant. CONCLUSION: Our results indicated that PCGF2: p.Pro65Leu might be a hotspot for GDD and highlighted the effect of this variant on protein function.
RESUMEN
Craniofacial morphogenesis is highly complex, as is the anatomical region involved. Errors during this process, resulting in orofacial clefts, occur in more than 400 genetic syndromes. Some cases of cleft lip and/or palate (CLP) are caused by mutations in single genes; however, complex interactions between genetic and environmental factors are considered to be responsible for the majority of non-syndromic CLP development. The aim of the current study was to identify genetic risk factors in patients with isolated cleft palate (CP) by whole genome sequencing. Patients with isolated CP (n = 30) recruited from the Riga Cleft Lip and Palate Centre, Institute of Stomatology, Riga, were analyzed by whole genome sequencing. Pathogenic or likely pathogenic variants were discovered in genes associated with CP (TBX22, COL2A1, FBN1, PCGF2, and KMT2D) in five patients; hence, rare disease variants were identified in 17% of patients with non-syndromic isolated CP. Our results were relevant to routine genetic counselling practice and genetic testing recommendations. Based on our data, we propose that all newborns with orofacial clefts should be offered genetic testing, at least for a panel of known CLP genes. Only if the results are negative and there is no suggestive family history or additional clinical symptoms (which would support additional exome or genome-wide investigation), should multifactorial empiric recurrence risk prediction tools be applied for families.