RESUMEN
Neuroendocrine (NE) prostate cancer (NEPC) is a lethal subtype of castration-resistant prostate cancer (PCa) arising either de novo or from transdifferentiated prostate adenocarcinoma following androgen deprivation therapy (ADT). Extensive computational analysis has identified a high degree of association between the long noncoding RNA (lncRNA) H19 and NEPC, with the longest isoform highly expressed in NEPC. H19 regulates PCa lineage plasticity by driving a bidirectional cell identity of NE phenotype (H19 overexpression) or luminal phenotype (H19 knockdown). It contributes to treatment resistance, with the knockdown of H19 re-sensitizing PCa to ADT. It is also essential for the proliferation and invasion of NEPC. H19 levels are negatively regulated by androgen signaling via androgen receptor (AR). When androgen is absent SOX2 levels increase, driving H19 transcription and facilitating transdifferentiation. H19 facilitates the PRC2 complex in regulating methylation changes at H3K27me3/H3K4me3 histone sites of AR-driven and NEPC-related genes. Additionally, this lncRNA induces alterations in genome-wide DNA methylation on CpG sites, further regulating genes associated with the NEPC phenotype. Our clinical data identify H19 as a candidate diagnostic marker and predictive marker of NEPC with elevated H19 levels associated with an increased probability of biochemical recurrence and metastatic disease in patients receiving ADT. Here we report H19 as an early upstream regulator of cell fate, plasticity, and treatment resistance in NEPC that can reverse/transform cells to a treatable form of PCa once therapeutically deactivated.
Asunto(s)
Carcinoma Neuroendocrino/genética , Carcinoma Neuroendocrino/patología , Plasticidad de la Célula/genética , Regulación Neoplásica de la Expresión Génica , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/patología , ARN Largo no Codificante/metabolismo , Antagonistas de Andrógenos/uso terapéutico , Animales , Benzamidas/farmacología , Benzamidas/uso terapéutico , Biomarcadores de Tumor/metabolismo , Carcinoma Neuroendocrino/diagnóstico , Carcinoma Neuroendocrino/tratamiento farmacológico , Línea Celular Tumoral , Linaje de la Célula/genética , Núcleo Celular/metabolismo , Proliferación Celular/genética , Estudios de Cohortes , Metilación de ADN/genética , Modelos Animales de Enfermedad , Resistencia a Antineoplásicos/genética , Epigénesis Genética/efectos de los fármacos , Genoma Humano , Histonas/metabolismo , Humanos , Masculino , Clasificación del Tumor , Invasividad Neoplásica , Células Madre Neoplásicas/metabolismo , Nitrilos/farmacología , Nitrilos/uso terapéutico , Organoides/metabolismo , Organoides/patología , Feniltiohidantoína/farmacología , Feniltiohidantoína/uso terapéutico , Filogenia , Complejo Represivo Polycomb 2/metabolismo , Regiones Promotoras Genéticas/genética , Neoplasias de la Próstata/diagnóstico , Neoplasias de la Próstata/tratamiento farmacológico , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , ARN Largo no Codificante/genética , Receptores Androgénicos/metabolismo , Factores de Transcripción SOXB1/metabolismo , Transcripción Genética/efectos de los fármacosRESUMEN
AIM: Development of a sensitive method for DNA methylation profiling and associated mutation detection in clinical samples. MATERIALS & METHODS: Formalin-fixed and paraffin-embedded tumors received by clinical laboratories often contain insufficient DNA for analysis with bisulfite or methylation sensitive restriction enzymes-based methods. To increase sensitivity, methyl-CpG DNA capture and Coupled Abscription PCR Signaling detection were combined in a new assay, MethylMeter(®). Gliomas were analyzed for MGMT methylation, glioma CpG island methylator phenotype and IDH1 R132H. RESULTS: MethylMeter had 100% assay success rate measuring all five biomarkers in formalin-fixed and paraffin-embedded tissue. MGMT methylation results were supported by survival and mRNA expression data. CONCLUSION: MethylMeter is a sensitive and quantitative method for multitarget DNA methylation profiling and associated mutation detection. The MethylMeter-based GliomaSTRAT assay measures methylation of four targets and one mutation to simultaneously grade gliomas and predict their response to temozolomide. This information is clinically valuable in management of gliomas.
