RESUMEN
Castration-resistant prostate cancer (CRPC) is a frequently occurring disease with adverse clinical outcomes and limited therapeutic options. Here, we identify methionine adenosyltransferase 2a (MAT2A) as a critical driver of the androgen-indifferent state in ERG fusion-positive CRPC. MAT2A is upregulated in CRPC and cooperates with ERG in promoting cell plasticity, stemness and tumorigenesis. RNA, ATAC and ChIP-sequencing coupled with histone post-translational modification analysis by mass spectrometry show that MAT2A broadly impacts the transcriptional and epigenetic landscape. MAT2A enhances H3K4me2 at multiple genomic sites, promoting the expression of pro-tumorigenic non-canonical AR target genes. Genetic and pharmacological inhibition of MAT2A reverses the transcriptional and epigenetic remodeling in CRPC models and improves the response to AR and EZH2 inhibitors. These data reveal a role of MAT2A in epigenetic reprogramming and provide a proof of concept for testing MAT2A inhibitors in CRPC patients to improve clinical responses and prevent treatment resistance.
Asunto(s)
Epigénesis Genética , Regulación Neoplásica de la Expresión Génica , Metionina Adenosiltransferasa , Neoplasias de la Próstata Resistentes a la Castración , Regulador Transcripcional ERG , Masculino , Humanos , Regulador Transcripcional ERG/genética , Regulador Transcripcional ERG/metabolismo , Metionina Adenosiltransferasa/genética , Metionina Adenosiltransferasa/metabolismo , Neoplasias de la Próstata Resistentes a la Castración/genética , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Neoplasias de la Próstata Resistentes a la Castración/metabolismo , Neoplasias de la Próstata Resistentes a la Castración/patología , Línea Celular Tumoral , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Epigénesis Genética/efectos de los fármacos , Animales , Andrógenos/metabolismo , Epigenoma , Ratones , Histonas/metabolismo , Receptores Androgénicos/metabolismo , Receptores Androgénicos/genética , Proteínas de Fusión Oncogénica/genética , Proteínas de Fusión Oncogénica/metabolismo , Proteína Potenciadora del Homólogo Zeste 2/metabolismo , Proteína Potenciadora del Homólogo Zeste 2/genética , Proteína Potenciadora del Homólogo Zeste 2/antagonistas & inhibidoresRESUMEN
Thoracic aortic aneurysms (TAAs) represent a serious health concern, as they are associated with early aortic dissection and rupture. TAA formation is triggered by genetic conditions, in particular Marfan syndrome (MFS) and bicuspid aortic valve (BAV). During the aneurysmatic process, aortic endothelial cells can undergo endothelial-to-mesenchymal transition (End-MT) with consequent phenotypic and functional alterations. We previously documented that MFS TAA is characterized by miR-632-driven End-MT exacerbation, whereas in BAV aortopathy, the occurrence of this process remains still controversial. We investigated the End-MT process and the underlined regulatory mechanisms in BAV, TAV and MFS TAA tissues. Gene expression and immunohistochemical analysis were performed in order to analyze some important miRNAs and genes characterizing End-MT. We documented that BAV endothelium maintains the expression of the endothelial homeostasis markers, such as ERG, CD31 and miR-126-5p, while it shows lower levels of miR-632 and mesenchymal markers compared with MFS. Interestingly, we also found higher levels of miR-632 in MFS patients' blood. Our findings definitively demonstrate that the End-MT process does not characterize BAV that, among the other TAAs, better maintains the endothelial features. In addition, our results suggest miR-632 as a promising diagnostic/prognostic factor in MFS aortopathy.
Asunto(s)
Aneurisma de la Aorta Torácica , Transición Epitelial-Mesenquimal , MicroARNs , Humanos , MicroARNs/genética , MicroARNs/metabolismo , Aneurisma de la Aorta Torácica/genética , Aneurisma de la Aorta Torácica/patología , Aneurisma de la Aorta Torácica/metabolismo , Transición Epitelial-Mesenquimal/genética , Masculino , Femenino , Persona de Mediana Edad , Células Endoteliales/metabolismo , Células Endoteliales/patología , Regulador Transcripcional ERG/metabolismo , Regulador Transcripcional ERG/genética , Enfermedad de la Válvula Aórtica Bicúspide/metabolismo , Enfermedad de la Válvula Aórtica Bicúspide/patología , Enfermedad de la Válvula Aórtica Bicúspide/genética , Anciano , Molécula-1 de Adhesión Celular Endotelial de Plaqueta/metabolismo , Adulto , Regulación de la Expresión Génica , Síndrome de Marfan/genética , Síndrome de Marfan/patología , Síndrome de Marfan/metabolismoRESUMEN
BACKGROUND: Shiga toxin (Stx) can activate inflammatory signaling, leading to vascular dysfunction and promotion of a pro-thrombotic tissue microenvironment. Stx can trigger the development of the enterohemorrhagic (childhood) hemolytic uremic syndrome (eHUS), a triad of thrombocytopenia, hemolytic anemia, and acute kidney injury, often requiring dialysis. Additional features may include damage to other organs, including the gastrointestinal tract, pancreas, brain and cardiovascular system; death occurs in 2-5 %. eHUS is a thrombotic microangiopathy; thus, endothelial cell (EC) injury and platelet fibrin thrombus formation in glomerular arterioles and in the arterioles of other affected organs are likely. To elucidate mechanisms of this microangiopathy, we examined in human ECs the regulation of the platelet adhesion proteins P-selectin and von Willebrand factor (VWF), along with the downregulation of erythroblast-transformation-specific transcription factor (ERG) a key regulator of angiogenesis and megakaryocyte development. METHODS: VWF, P-selectin, and ERG levels were determined using immunofluorescence and Western blot in human umbilical endothelial cells (HUVECs). HUVECs were treated with tumor necrosis factor-alpha (TNF-α), Stx-1 or both, versus normal controls. Capillary morphogenesis on Matrigel was performed using HUVECs treated, for 22 h with TNF-α, Stx-1, or both, or treated 4 h with Stx-1 alone or in combination with TNF-α for 22 h. RESULTS: Stx-1 significantly reduced ERG and VWF expression on HUVECs, but upregulated P-selectin expression. ERG levels decreased with Stx-1 alone or in combination with TNF-α, in the nuclear, perinuclear and cytoplasmatic regions. Stx-1 reduced capillary morphogenesis, while Stx-1-TNF-α combined treatment reduced capillary morphogenesis still further. CONCLUSIONS: In the presence of Stx-1 or TNF-α or both treatments, ECs were activated, expressing higher levels of P-selectin and lower levels of VWF. Our findings, further, provide evidence that Stx-1 downregulates ERG, repressing angiogenesis in vitro.
Asunto(s)
Regulación hacia Abajo , Células Endoteliales de la Vena Umbilical Humana , Humanos , Regulación hacia Abajo/efectos de los fármacos , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Regulador Transcripcional ERG/metabolismo , Toxina Shiga/metabolismo , Toxina Shiga/farmacología , Células Endoteliales/metabolismo , Células Endoteliales/efectos de los fármacos , Factor de von Willebrand/metabolismo , AngiogénesisRESUMEN
Endothelial cells are a heterogeneous population with various organ-specific and conserved functions that are critical to organ development, function, and regeneration. Here we report a Sox17-Erg direct reprogramming approach that uses cardiac fibroblasts to create differentiated endothelial cells that demonstrate endothelial-like molecular and physiological functions in vitro and in vivo. Injection of these induced endothelial cells into myocardial infarct sites after injury results in improved vascular perfusion of the scar region. Furthermore, we use genomic analyses to illustrate that Sox17-Erg reprogramming instructs cardiac fibroblasts toward an arterial-like identity. This results in a more efficient direct conversion of fibroblasts into endothelial-like cells when compared to traditional Etv2-based reprogramming. Overall, this Sox17-Erg direct reprogramming strategy offers a robust tool to generate endothelial cells both in vitro and in vivo, and has the potential to be used in repairing injured tissue.
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Reprogramación Celular , Células Endoteliales , Fibroblastos , Factores de Transcripción SOXF , Regulador Transcripcional ERG , Animales , Ratones , Diferenciación Celular , Reprogramación Celular/genética , Células Endoteliales/metabolismo , Células Endoteliales/citología , Fibroblastos/metabolismo , Fibroblastos/citología , Proteínas HMGB/metabolismo , Proteínas HMGB/genética , Ratones Endogámicos C57BL , Infarto del Miocardio/patología , Miocardio/citología , Miocardio/metabolismo , Factores de Transcripción SOXF/metabolismo , Factores de Transcripción SOXF/genética , Regulador Transcripcional ERG/genética , Regulador Transcripcional ERG/metabolismoRESUMEN
BACKGROUND: Some studies confirmed that erythroblast transformation-specific-related gene (ERG) may be a pathogenic factor of oral squamous cell carcinoma (OSCC). However, the undergoing molecular mechanism has not been elucidated yet. OBJECTIVE: In this study, the investigation will focus on how the transcription factor ERG modulates the biological behaviors of OSCC. METHODS: In this study, cancer tissue specimens and corresponding paracancer tissues were collected from 54 patients. Real-time polymerase chain reaction analysis and Western blots were employed to detect the expression of multiple genes. Cell proliferation assays, Transwell, and flow cytometry assay were utilized to detect the proliferation, invasion, and apoptosis of OSCC cell, respectively. Dual luciferase reporter gene and chromatin immunoprecipitation assays were conducted to verify the regulation of ERG on PRDX1. RESULTS: ERG exhibits high expression levels in OSCC. Inhibition of ERG has been shown to effectively suppress the malignant growth of OSCC cells. Moreover, ERG has been found to transcriptionally upregulate the expression of PRDX1. The knockdown of PRDX1 has demonstrated its ability to inhibit the malignant growth of OSCC cells. Interestingly, when PRDX1 is overexpressed, it attenuates the inhibitory effect of si-ERG on the malignant growth of OSCC cells. This suggests that PRDX1 may play a crucial role in mediating the impact of ERG on malignancy in OSCC cells. CONCLUSION: The transcription factor ERG promotes the expression of PRDX1, which could enhance the proliferation and invasion while inhibiting the apoptosis of OSCC cells.
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Carcinoma de Células Escamosas , Proliferación Celular , Neoplasias de la Boca , Peroxirredoxinas , Regulador Transcripcional ERG , Regulación hacia Arriba , Humanos , Peroxirredoxinas/genética , Peroxirredoxinas/metabolismo , Neoplasias de la Boca/patología , Neoplasias de la Boca/genética , Neoplasias de la Boca/metabolismo , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patología , Carcinoma de Células Escamosas/metabolismo , Regulador Transcripcional ERG/genética , Regulador Transcripcional ERG/metabolismo , Apoptosis/genética , Línea Celular Tumoral , Regulación Neoplásica de la Expresión Génica , Metástasis de la Neoplasia , Invasividad Neoplásica , Activación Transcripcional , Femenino , MasculinoRESUMEN
BACKGROUND: Prostate cancer is the leading cause of cancer-related death and the second most commonly diagnosed cancer among men in Uganda and most countries in Sub-Saharan Africa (SSA). The TMPRSS2-ERG fusion gene is the most common genetic alteration seen among prostate cancer patients. There are several contradicting reports about the association of ERG protein with poor prognosis, high PSA, and Gleason score. This study determined the prevalence of ERG expression and the relationship with PSA, Gleason score, and Age of prostate cancer patients in Southwestern Uganda. METHODS: We reviewed 130 archived prostate biopsy (needle and TURP) specimens from patients of age ≥ 50 years who had a histological diagnosis of prostate cancer. We obtained their biodata, and preoperative PSA, from the archived records. We did Immunohistochemistry (IHC) to determine the prevalence of ERG expression. RESULTS: The mean patient age in our study was 74.64 ± 10.19 years. Pre-operative PSA levels had been done for 79.2% of the participants. Most cancers (58.46%) were of high grade (grade group 3-5). ERG expression prevalence was 75.4% and its expression was independent of age, re-operative PSA, and Gleason score. CONCLUSION: There is a significantly higher prevalence of ERG expression in our study compared to what is reported in other African-based studies. The expression of the ERG is independent of age, Gleason score, and serum PSA levels. A high proportion of our prostate cancer has high-grade disease at the time of diagnosis.
Asunto(s)
Biomarcadores de Tumor , Clasificación del Tumor , Neoplasias de la Próstata , Regulador Transcripcional ERG , Humanos , Masculino , Neoplasias de la Próstata/patología , Neoplasias de la Próstata/epidemiología , Neoplasias de la Próstata/genética , Regulador Transcripcional ERG/genética , Uganda/epidemiología , Estudios Transversales , Anciano , Persona de Mediana Edad , Biomarcadores de Tumor/análisis , Anciano de 80 o más Años , Antígeno Prostático Específico/sangre , InmunohistoquímicaRESUMEN
During hematopoiesis, megakaryocytic erythroid progenitors (MEPs) differentiate into megakaryocytic or erythroid lineages in response to specific transcriptional factors, yet the regulatory mechanism remains to be elucidated. Using the MEPlike cell line HEL western blotting, RTqPCR, lentivirusmediated downregulation, flow cytometry as well as chromatin immunoprecipitation (ChIp) assay demonstrated that the E26 transformationspecific (ETS) transcription factor friend leukemia integration factor 1 (Fli1) inhibits erythroid differentiation. The present study using these methods showed that while FLI1mediated downregulation of GATA binding protein 1 (GATA1) suppresses erythropoiesis, its direct transcriptional induction of GATA2 promotes megakaryocytic differentiation. GATA1 is also involved in megakaryocytic differentiation through regulation of GATA2. By contrast to FLI1, the ETS member erythroblast transformationspecificrelated gene (ERG) negatively controls GATA2 and its overexpression through exogenous transfection blocks megakaryocytic differentiation. In addition, FLI1 regulates expression of LIM Domain Binding 1 (LDB1) during erythroid and megakaryocytic commitment, whereas shRNAmediated depletion of LDB1 downregulates FLI1 and GATA2 but increases GATA1 expression. In agreement, LDB1 ablation using shRNA lentivirus expression blocks megakaryocytic differentiation and modestly suppresses erythroid maturation. These results suggested that a certain threshold level of LDB1 expression enables FLI1 to block erythroid differentiation. Overall, FLI1 controlled the commitment of MEP to either erythroid or megakaryocytic lineage through an intricate regulation of GATA1/GATA2, LDB1 and ERG, exposing multiple targets for cell fate commitment and therapeutic intervention.
Asunto(s)
Diferenciación Celular , Células Eritroides , Megacariocitos , Humanos , Diferenciación Celular/genética , Línea Celular , Células Eritroides/metabolismo , Células Eritroides/citología , Factor de Transcripción GATA1/metabolismo , Factor de Transcripción GATA1/genética , Factor de Transcripción GATA2/metabolismo , Factor de Transcripción GATA2/genética , Regulación de la Expresión Génica , Proteínas con Dominio LIM/metabolismo , Proteínas con Dominio LIM/genética , Megacariocitos/metabolismo , Megacariocitos/citología , Proteína Proto-Oncogénica c-fli-1/metabolismo , Proteína Proto-Oncogénica c-fli-1/genética , Regulador Transcripcional ERG/metabolismo , Regulador Transcripcional ERG/genéticaRESUMEN
Aberrant expression of the E26 transformation-specific (ETS) transcription factors characterizes numerous human malignancies. Many of these proteins, including EWS:FLI1 and EWS:ERG fusions in Ewing sarcoma (EwS) and TMPRSS2:ERG in prostate cancer (PCa), drive oncogenic programs via binding to GGAA repeats. We report here that both EWS:FLI1 and ERG bind and transcriptionally activate GGAA-rich pericentromeric heterochromatin. The respective pathogen-like HSAT2 and HSAT3 RNAs, together with LINE, SINE, ERV, and other repeat transcripts, are expressed in EwS and PCa tumors, secreted in extracellular vesicles (EVs), and are highly elevated in plasma of patients with EwS with metastatic disease. High human satellite 2 and 3 (HSAT2,3) levels in EWS:FLI1- or ERG-expressing cells and tumors were associated with induction of G2/M checkpoint, mitotic spindle, and DNA damage programs. These programs were also activated in EwS EV-treated fibroblasts, coincident with accumulation of HSAT2,3 RNAs, proinflammatory responses, mitotic defects, and senescence. Mechanistically, HSAT2,3-enriched cancer EVs induced cGAS-TBK1 innate immune signaling and formation of cytosolic granules positive for double-strand RNAs, RNA-DNA, and cGAS. Hence, aberrantly expressed ETS proteins derepress pericentromeric heterochromatin, yielding pathogenic RNAs that transmit genotoxic stress and inflammation to local and distant sites. Monitoring HSAT2,3 plasma levels and preventing their dissemination may thus improve therapeutic strategies and blood-based diagnostics.
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Daño del ADN , Vesículas Extracelulares , Proteínas de Fusión Oncogénica , Proteína Proto-Oncogénica c-fli-1 , Proteína EWS de Unión a ARN , Regulador Transcripcional ERG , Humanos , Vesículas Extracelulares/metabolismo , Vesículas Extracelulares/genética , Proteínas de Fusión Oncogénica/genética , Proteínas de Fusión Oncogénica/metabolismo , Regulador Transcripcional ERG/genética , Regulador Transcripcional ERG/metabolismo , Masculino , Proteína EWS de Unión a ARN/genética , Proteína EWS de Unión a ARN/metabolismo , Proteína Proto-Oncogénica c-fli-1/genética , Proteína Proto-Oncogénica c-fli-1/metabolismo , Sarcoma de Ewing/genética , Sarcoma de Ewing/patología , Sarcoma de Ewing/metabolismo , Sarcoma de Ewing/inmunología , Línea Celular Tumoral , ARN Neoplásico/genética , ARN Neoplásico/metabolismo , Inflamación/genética , Inflamación/metabolismo , Inflamación/patología , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/patología , Neoplasias de la Próstata/metabolismo , Ratones , Animales , Heterocromatina/metabolismo , Heterocromatina/genéticaRESUMEN
Philadelphia chromosome-positive B cell acute lymphoblastic leukemia (B-ALL), characterized by the BCR::ABL1 fusion gene, remains a poor prognosis cancer needing new therapeutic approaches. Transcriptomic profiling identified up-regulation of oncogenic transcription factors ERG and c-MYC in BCR::ABL1 B-ALL with ERG and c-MYC required for BCR::ABL1 B-ALL in murine and human models. Profiling of ERG- and c-MYC-dependent gene expression and analysis of ChIP-seq data established ERG and c-MYC coordinate a regulatory network in BCR::ABL1 B-ALL that controls expression of genes involved in several biological processes. Prominent was control of ribosome biogenesis, including expression of RNA polymerase I (POL I) subunits, the importance of which was validated by inhibition of BCR::ABL1 cells by POL I inhibitors, including CX-5461, that prevents promoter recruitment and transcription initiation by POL I. Our results reveal an essential ERG- and c-MYC-dependent transcriptional network involved in regulation of metabolic and ribosome biogenesis pathways in BCR::ABL1 B-ALL, from which previously unidentified vulnerabilities and therapeutic targets may emerge.
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Proteínas de Fusión bcr-abl , Leucemia-Linfoma Linfoblástico de Células Precursoras B , Regulador Transcripcional ERG , Animales , Humanos , Ratones , Proteínas de Fusión bcr-abl/genética , Proteínas de Fusión bcr-abl/metabolismo , Proteínas de Fusión bcr-abl/uso terapéutico , Redes Reguladoras de Genes , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras , Factores de Transcripción/genética , Regulador Transcripcional ERG/genéticaRESUMEN
Lymphatic metastasis is a common metastasis of lung adenocarcinoma (LUAD). The current study illustrated the action of lncRNA NKX2-1-AS1 in lymphangiogenesis in LUAD and the underlying mechanisms. Clinical tissue samples were collected for determining NKX2-1-AS1 expression. Then, H441 and H661 cells were selected to perform gain- and loss-of-function assays for dissecting the roles of NKX2-1-AS1 in LUAD cell proliferation and migration. Besides, H441 and H661 cell supernatant was harvested to stimulate HLECs for assessing tube formation ability. Interaction among NKX2-1-AS1, ERG, and fatty acid binding protein 4 (FABP4) was validated through luciferase and RIP assays. NKX2-1-AS1 was highly-expressed in LUAD tissues. Silencing NKX2-1-AS1 suppressed H441 and H661 cell proliferation and migration, reduced expression levels of lymphangiogenesis-related factors (LYVE-1, VEGF-C, VEGFR3, VEGF-A, VEGFR2, and CCR7), and inhibited HLEC tube formation. Interaction validation demonstrated that NKX2-1-AS1 regulated FABP4 transcription by binding to ERG. Overexpression of FABP4 could effectively block the inhibition role of NKX2-1-AS1 silencing in lymphangiogenesis in H441 and H661 cells. This study provided evidence that NKX2-1-AS1 regulated FABP4 transcription by binding to ERG to facilitate the proliferation and migration of LUAD cells and tube formation of HLECs, thus participating in lymphangiogenesis.
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Adenocarcinoma , Neoplasias Pulmonares , MicroARNs , ARN Largo no Codificante , Humanos , Adenocarcinoma/genética , Línea Celular Tumoral , Proliferación Celular/genética , Proteínas de Unión a Ácidos Grasos/genética , Proteínas de Unión a Ácidos Grasos/metabolismo , Regulación Neoplásica de la Expresión Génica , Pulmón/patología , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Linfangiogénesis/genética , MicroARNs/genética , ARN Largo no Codificante/genética , Regulador Transcripcional ERG/genética , Regulador Transcripcional ERG/metabolismoRESUMEN
To assess full-field electroretinogram findings in long-term type 1 diabetes patients without diabetic retinopathy. Prospective study including 46 eyes of 23 patients with type 1 diabetes and 46 age-matched healthy eyes evaluated by the RETI-port/scan21 and the portable system RETeval following ISCEV guidelines. The average duration of diabetes was 28.88 ± 8.04 years. In scotopic conditions, using the RETI-port/scan21, diabetic patients showed an increase in b-wave implicit time (IT) (p = 0.017) with the lowest stimuli; a diminished b-wave amplitude (p = 0.005) in the mixed response, an increased IT (p = 0.004) with the high-intensity stimuli and an OP2 increased IT (p = 0.008) and decreased amplitude (p = 0.002). Under photopic conditions, b-wave amplitude was lower (p < 0.001) and 30-Hz flicker response was diminished (p = 0.021). Using the RETeval, in scotopic conditions, diabetic patients showed a reduction in the rod b-wave amplitude (p = 0.009), an increase in a-wave IT with the 280 Td.s stimulus (p = 0.005). OP2 had an increased IT and diminished amplitude (p = 0.003 and p = 0.002 respectively). 16 Td.s flicker showed an increased IT (p = 0.008) and diminished amplitude (p = 0.048). Despite variations in values between both systems, nearly all results displayed positive correlations. Long-term type 1 diabetes patients without diabetic retinopathy exhibit alterations in scotopic conditions, as evidenced by both conventional and portable electroretinogram devices. These findings suggest a modified retinal function, particularly in rod-driven pathways, even in the absence of vascular signs.
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Diabetes Mellitus Tipo 1 , Retinopatía Diabética , Humanos , Retinopatía Diabética/diagnóstico , Estudios Prospectivos , Retina , Electrorretinografía , Estimulación Luminosa , Regulador Transcripcional ERGRESUMEN
BACKGROUND: TMPRSS2-ERG (T2E) fusion is highly related to aggressive clinical features in prostate cancer (PC), which guides individual therapy. However, current fusion prediction tools lacked enough accuracy and biomarkers were unable to be applied to individuals across different platforms due to their quantitative nature. This study aims to identify a transcriptome signature to detect the T2E fusion status of PC at the individual level. METHODS: Based on 272 high-throughput mRNA expression profiles from the Sboner dataset, we developed a rank-based algorithm to identify a qualitative signature to detect T2E fusion in PC. The signature was validated in 1223 samples from three external datasets (Setlur, Clarissa, and TCGA). RESULTS: A signature, composed of five mRNAs coupled to ERG (five ERG-mRNA pairs, 5-ERG-mRPs), was developed to distinguish T2E fusion status in PC. 5-ERG-mRPs reached 84.56% accuracy in Sboner dataset, which was verified in Setlur dataset (n = 455, accuracy = 82.20%) and Clarissa dataset (n = 118, accuracy = 81.36%). Besides, for 495 samples from TCGA, two subtypes classified by 5-ERG-mRPs showed a higher level of significance in various T2E fusion features than subtypes obtained through current fusion prediction tools, such as STAR-Fusion. CONCLUSIONS: Overall, 5-ERG-mRPs can robustly detect T2E fusion in PC at the individual level, which can be used on any gene measurement platform without specific normalization procedures. Hence, 5-ERG-mRPs may serve as an auxiliary tool for PC patient management.
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Neoplasias de la Próstata , Transcriptoma , Masculino , Humanos , Proteínas de Fusión Oncogénica/genética , Proteínas de Fusión Oncogénica/metabolismo , Proteínas de Fusión Oncogénica/uso terapéutico , Neoplasias de la Próstata/tratamiento farmacológico , ARN Mensajero/genética , Regulador Transcripcional ERG/genética , Regulador Transcripcional ERG/metabolismo , Serina Endopeptidasas/genética , Serina Endopeptidasas/metabolismo , Serina Endopeptidasas/uso terapéuticoRESUMEN
IMPLICATIONS: Our study illuminates the potential of deep learning in effectively inferring key prostate cancer genetic alterations from the tissue morphology depicted in routinely available histology slides, offering a cost-effective method that could revolutionize diagnostic strategies in oncology.
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Aprendizaje Profundo , Neoplasias de la Próstata , Masculino , Humanos , Proteínas de Fusión Oncogénica/genética , Neoplasias de la Próstata/patología , Prostatectomía , Regulador Transcripcional ERG , Serina Endopeptidasas/genéticaRESUMEN
Background and Objectives: Prognostic biomarkers in prostate cancer (PCa) include PTEN, ERG, SPINK1, and TFF3. Their relationships and patterns of expression in PCa in developing countries, including Jordan, have not yet been investigated. Materials and Methods: A tissue microarray (TMA) of PCa patients was taken from paraffin-embedded tissue blocks for 130 patients. PTEN, ERG, SPINK1, and TFF3 expression profiles were examined using immunohistochemistry (IHC) and correlated with each other and other clinicopathological factors. Results: PTEN loss of any degree was observed in 42.9% of PCa cases. ERG and TFF3 were expressed in 59.3% and 46.5% of PCa cases, respectively. SPINK1 expression was observed in 6 out of 104 PCa cases (5.4%). Among all PCa cases (n = 104), 3.8% (n = 4) showed SPINK1+/ERG+ phenotype, 1.9% (n = 2) showed SPINK1+/ERG- phenotype, 56.7% (n = 59) showed SPINK1-/ERG+ phenotype, and 37.5% showed SPINK1-/ERG- phenotype (n = 39). Among ERG positive cases (n = 63), 6.3% were SPINK1 positive. Among SPINK1 positive cases (n = 6), 66.7% were ERG positive. SPINK1 expression was predominantly observed in a subgroup of cancers that expressed TFF3 (6/6). Additionally, a statistically significant loss of PTEN expression was observed from Gleason Score 6 (GS6) (Grade Group 1 (GG1)) to GS9-10 (GG5); (p-value 0.019). Conclusions: This is the first study to look at the status of the PTEN, ERG, SPINK1, and TFF3 genes in a Jordanian Arab population. Loss of PTEN has been linked to more aggressive prostate cancer with high GSs/GGs. SPINK1 expression was predominantly observed in a subgroup of cancers that expressed TFF3. Our results call for screening these biomarkers for grading and molecular subtyping of the disease.
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Neoplasias de la Próstata , Inhibidor de Tripsina Pancreática de Kazal , Masculino , Humanos , Inhibidor de Tripsina Pancreática de Kazal/genética , Jordania , Árabes , Biomarcadores , Regulador Transcripcional ERG/genética , Factor Trefoil-3 , Fosfohidrolasa PTEN/genéticaRESUMEN
BACKGROUND: Although the fusion of the transmembrane serine protease 2 gene (TMPRSS2) with the erythroblast transformation-specific-related gene (ERG), or TMPRSS2-ERG, occurs frequently in prostate cancer, its impact on clinical outcomes remains controversial. Roughly half of TMPRSS2-ERG fusions occur through intrachromosomal deletion of interstitial genes and the remainder via insertional chromosomal rearrangements. Because prostate cancers with deletion-derived TMPRSS2-ERG fusions are more aggressive than those with insertional fusions, we investigated the impact of interstitial gene loss on prostate cancer progression. METHODS: We conducted an unbiased analysis of transcriptome data from large collections of prostate cancer samples and employed diverse in vitro and in vivo models combined with genetic approaches to characterize the interstitial gene loss that imposes the most important impact on clinical outcome. RESULTS: This analysis identified FAM3B as the top-ranked interstitial gene whose loss is associated with a poor prognosis. The association between FAM3B loss and poor clinical outcome extended to fusion-negative prostate cancers where FAM3B downregulation occurred through epigenetic imprinting. Importantly, FAM3B loss drives disease progression in prostate cancer. FAM3B acts as an intermediator of a self-governing androgen receptor feedback loop. Specifically, androgen receptor upregulates FAM3B expression by binding to an intronic enhancer to induce an enhancer RNA and facilitate enhancer-promoter looping. FAM3B, in turn, attenuates androgen receptor signaling. CONCLUSION: Loss of FAM3B in prostate cancer, whether through the TMPRSS2-ERG translocation or epigenetic imprinting, causes an exit from this autoregulatory loop to unleash androgen receptor activity and prostate cancer progression. These findings establish FAM3B loss as a new driver of prostate cancer progression and support the utility of FAM3B loss as a biomarker to better define aggressive prostate cancer.
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Neoplasias de la Próstata , Receptores Androgénicos , Masculino , Humanos , Receptores Androgénicos/genética , Retroalimentación , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/metabolismo , Transcriptoma , Proteínas de Fusión Oncogénica/genética , Regulador Transcripcional ERG/genética , Regulador Transcripcional ERG/metabolismo , Proteínas de Neoplasias/genética , Citocinas/genéticaRESUMEN
PURPOSE: Prostate cancer (PCa) is the leading cause of death among men in 48 countries. Genetic alterations play a significant role in PCa carcinogenesis. For the hypothesis of this research, five unique polymorphisms (SNP) were investigated in different genes that showed to be associated in different ways with PCa: rs4430796, rs2735839, rs4792311, rs12329760, and rs28931588, respectively for the genes HNF1B, KLK3, ELAC2, TMPRSS2-ERG, and CTNNB1. PATIENTS AND METHODS: Blood samples from 426 subjects were evaluated: 290 controls (161 females and 129 males) and 136 PCa patients. SNP were determined by real-time polymerase chain reaction. TaqMan SNP genotyping assay. In the control samples, the SNPs were defined in association with the self-reported ethnicity, and in 218 control samples with markers with ancestry indicators. The genes were in Hardy-Weinberg equilibrium. One hundred and seventy control samples were matched by ethnicity for comparison with the PCa samples. RESULTS: The G allele at rs28931588 was monomorphic in both patients and controls studied. Significant differences were observed in allelic and genotypic frequencies between the control and Pca samples in rs2735839 (KLK3; p = 0.002 and χ2 = 8.73 and p = 0.01, respectively), by the global frequency and in the dominant model rs2735839_GG (odds ratio [OR] = 0.51, p = 0.02). AA and GA genotypes at rs4792311 (ELAC2) were more frequent in patients with Gleason 7(4 + 3), 8, and 9 (n = 37%-59.7%) compared to patients with Gleason 6 and 7(3 + 4) (n = 26%-40.0%) conferring a protective effect on the GG genotype (OR = 0.45, p = 0.02). The same genotype showed an OR = 2.71 (p = 0.01) for patients with low severity. The HNF1B-KLK3-ELAC2-TMPRSS2-ERG haplotypes: GAAT, AAAT, GAGT, and AAGT were more frequent in patients with Pca with OR ranging from 4.65 to 2.48. CONCLUSIONS: Higher frequencies of risk alleles were confirmed in the SNPs, KLK3 rs2735839_A, ELAC2 rs4792311_A, and TMPRSS2 rs12329760_T in patients with Pca. Rs2735839_A was associated with risk of Pca and rs4792311_A with severity and Gleason score of 7(4 + 3) or greater. There is a need for careful observation of rs2735839 and rs4792311 in association with the prostatic biopsy due to the increased risk of Pca.
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Antígeno Prostático Específico , Neoplasias de la Próstata , Masculino , Humanos , Calicreínas/genética , Predisposición Genética a la Enfermedad , Neoplasias de la Próstata/patología , Genotipo , Polimorfismo de Nucleótido Simple , Regulador Transcripcional ERG/genética , Factor Nuclear 1-beta del Hepatocito/genética , Proteínas de Neoplasias , beta Catenina/genéticaRESUMEN
AIM: Bradyarrhythmias result from inhibition of automaticity, prolonged repolarization, or slow conduction in the heart. The ERG channels mediate the repolarizing current IKr in the cardiac action potential, whereas T-type calcium channels (TTCC) are involved in the sinoatrial pacemaker and atrioventricular conduction in mammals. Zebrafish have become a valuable research model for human cardiac electrophysiology and disease. Here, we investigate the contribution of ERG channels and TTCCs to the pacemaker and atrioventricular conduction in zebrafish larvae and determine the mechanisms causing atrioventricular block. METHODS: Zebrafish larvae expressing ratiometric fluorescent Ca2+ biosensors in the heart were used to measure Ca2+ levels and rhythm in beating hearts in vivo, concurrently with contraction and hemodynamics. The atrioventricular delay (the time between the start of atrial and ventricular Ca2+ transients) was used to measure impulse conduction velocity and distinguished between slow conduction and prolonged refractoriness as the cause of the conduction block. RESULTS: ERG blockers caused bradycardia and atrioventricular block by prolonging the refractory period in the atrioventricular canal and in working ventricular myocytes. In contrast, inhibition of TTCCs caused bradycardia and second-degree block (Mobitz type I) by slowing atrioventricular conduction. TTCC block did not affect ventricular contractility, despite being highly expressed in cardiomyocytes. Concomitant measurement of Ca2+ levels and ventricular size showed mechano-mechanical coupling: increased preload resulted in a stronger heart contraction in vivo. CONCLUSION: ERG channels and TTCCs influence the heart rate and atrioventricular conduction in zebrafish larvae. The zebrafish lines expressing Ca2+ biosensors in the heart allow us to investigate physiological feedback mechanisms and complex arrhythmias.
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Bloqueo Atrioventricular , Canales de Calcio Tipo T , Marcapaso Artificial , Humanos , Animales , Pez Cebra , Frecuencia Cardíaca/fisiología , Bradicardia , Canales de Calcio Tipo T/fisiología , Canales de Potasio Éter-A-Go-Go , Miocitos Cardíacos , Mamíferos , Regulador Transcripcional ERGRESUMEN
This study aimed to investigate the role of ERG in the HLX/STAT4/Perforin signaling axis, impacting natural killer (NK) cell cytotoxicity and myocardial infarction (MI) progression. NK cell cytotoxicity was assessed via co-culture and 51Cr release assays. Datasets GSE34198 and GSE97320 identified common differentially expressed genes in MI. NK cell gene expression was analyzed in MI patients and healthy individuals using qRT-PCR and Western blotting. ERG's regulation of HLX and STAT4's regulation of perforin were studied through computational tools (MEM) and ChIP experiments. HLX's influence on STAT4 was explored with the MG132 proteasome inhibitor. Findings were validated in a mouse MI model.ERG, a commonly upregulated gene, was identified in NK cells from MI patients and mice. ERG upregulated HLX, leading to STAT4 proteasomal degradation and reduced Perforin expression. Consequently, NK cell cytotoxicity decreased, promoting MI progression. ERG mediates the HLX/STAT4/Perforin axis to inhibit NK cell cytotoxicity, fostering MI progression. These results provide vital insights into MI's molecular mechanisms.
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Citotoxicidad Inmunológica , Células Asesinas Naturales , Animales , Humanos , Ratones , Proteínas de Homeodominio , Células Asesinas Naturales/metabolismo , Perforina/genética , Perforina/metabolismo , Transducción de Señal , Factor de Transcripción STAT4/genética , Factor de Transcripción STAT4/metabolismo , Factores de Transcripción/metabolismo , Regulador Transcripcional ERG/metabolismoRESUMEN
SND1 and MTDH are known to promote cancer and therapy resistance, but their mechanisms and interactions with other oncogenes remain unclear. Here, we show that oncoprotein ERG interacts with SND1/MTDH complex through SND1's Tudor domain. ERG, an ETS-domain transcription factor, is overexpressed in many prostate cancers. Knocking down SND1 in human prostate epithelial cells, especially those overexpressing ERG, negatively impacts cell proliferation. Transcriptional analysis shows substantial overlap in genes regulated by ERG and SND1. Mechanistically, we show that ERG promotes nuclear localization of SND1/MTDH. Forced nuclear localization of SND1 prominently increases its growth promoting function irrespective of ERG expression. In mice, prostate-specific Snd1 deletion reduces cancer growth and tumor burden in a prostate cancer model (PB-Cre/Ptenflox/flox/ERG mice), Moreover, we find a significant overlap between prostate transcriptional signatures of ERG and SND1. These findings highlight SND1's crucial role in prostate tumorigenesis, suggesting SND1 as a potential therapeutic target in prostate cancer.
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Neoplasias de la Próstata , Animales , Humanos , Masculino , Ratones , Transformación Celular Neoplásica/genética , Endonucleasas/genética , Endonucleasas/metabolismo , Regulación Neoplásica de la Expresión Génica , Proteínas de la Membrana/metabolismo , Próstata/patología , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/patología , Proteínas de Unión al ARN/metabolismo , Factores de Transcripción/metabolismo , Regulador Transcripcional ERG/genética , Regulador Transcripcional ERG/metabolismo , Dominio TudorRESUMEN
The ETS transcription factor ERG is aberrantly expressed in approximately 50% of prostate tumors due to chromosomal rearrangements such as TMPRSS2/ERG. The ability of ERG to drive oncogenesis in prostate epithelial cells requires interaction with distinct coactivators, such as the RNA-binding protein EWS. Here, we find that ERG has both direct and indirect interactions with EWS, and the indirect interaction is mediated by the poly-A RNA-binding protein PABPC1. PABPC1 directly bound both ERG and EWS. ERG expression in prostate cells promoted PABPC1 localization to the nucleus and recruited PABPC1 to ERG/EWS-binding sites in the genome. Knockdown of PABPC1 in prostate cells abrogated ERG-mediated phenotypes and decreased the ability of ERG to activate transcription. These findings define a complex including ERG and the RNA-binding proteins EWS and PABPC1 that represents a potential therapeutic target for ERG-positive prostate cancer and identify a novel nuclear role for PABPC1.