RESUMEN
Neuroblastoma is one of only a few human cancers that can spontaneously regress even after extensive dissemination, a poorly understood phenomenon that occurs in as many as 10% of patients. In this study, we identify the TALE-homeodomain transcription factor MEIS2 as a key contributor to this phenomenon. We identified MEIS2 as a MYCN-independent factor in neuroblastoma and showed that in this setting the alternatively spliced isoforms MEIS2A and MEIS2D exert antagonistic functions. Specifically, expression of MEIS2A was low in aggressive stage 4 neuroblastoma but high in spontaneously regressing stage 4S neuroblastoma. Moderate elevation of MEIS2A expression reduced proliferation of MYCN-amplified human neuroblastoma cells, induced neuronal differentiation and impaired the ability of these cells to form tumors in mice. In contrast, MEIS2A silencing or MEIS2D upregulation enhanced the aggressiveness of the tumor phenotype. Mechanistically, MEIS2A uncoupled a negative feedback loop that restricts accumulation of cellular retinoic acid, an effective agent in neuroblastoma treatment. Overall, our results illuminate the basis for spontaneous regression in neuroblastoma and identify an MEIS2A-specific signaling network as a potential therapeutic target in this common pediatric malignancy.Significance: This study illuminates the basis for spontaneous regressions that can occur in a common pediatric tumor, with implications for the development of new treatment strategies. Cancer Res; 78(8); 1935-47. ©2018 AACR.
Asunto(s)
Carcinogénesis , Proteínas de Homeodominio/fisiología , Neuroblastoma/patología , Isoformas de Proteínas/fisiología , Factores de Transcripción/fisiología , Empalme Alternativo , Animales , Diferenciación Celular/fisiología , Línea Celular Tumoral , Proliferación Celular , Exones , Técnicas de Silenciamiento del Gen , Silenciador del Gen , Proteínas de Homeodominio/química , Proteínas de Homeodominio/genética , Humanos , Masculino , Ratones , Ratones Desnudos , Neuroblastoma/metabolismo , Pronóstico , Isoformas de Proteínas/química , Isoformas de Proteínas/genética , ARN Mensajero/genética , Factores de Transcripción/química , Factores de Transcripción/genética , Tretinoina/metabolismoRESUMEN
Adult neurogenesis is regulated by stem cell niche-derived extrinsic factors and cell-intrinsic regulators, yet the mechanisms by which niche signals impinge on the activity of intrinsic neurogenic transcription factors remain poorly defined. Here, we report that MEIS2, an essential regulator of adult SVZ neurogenesis, is subject to posttranslational regulation in the SVZ olfactory bulb neurogenic system. Nuclear accumulation of MEIS2 in adult SVZ-derived progenitor cells follows downregulation of EGFR signaling and is modulated by methylation of MEIS2 on a conserved arginine, which lies in close proximity to nested binding sites for the nuclear export receptor CRM1 and the MEIS dimerization partner PBX1. Methylation impairs interaction with CRM1 without affecting PBX1 dimerization and thereby allows MEIS2 nuclear accumulation, a prerequisite for neuronal differentiation. Our results describe a form of posttranscriptional modulation of adult SVZ neurogenesis whereby an extrinsic signal fine-tunes neurogenesis through posttranslational modification of a transcriptional regulator of cell fate.
Asunto(s)
Arginina/metabolismo , Diferenciación Celular , Núcleo Celular/metabolismo , Proteínas de Homeodominio/metabolismo , Ventrículos Laterales/citología , Células-Madre Neurales/citología , Neuronas/citología , Secuencia de Aminoácidos , Animales , Unión Competitiva , Receptores ErbB/metabolismo , Proteínas de Homeodominio/química , Carioferinas/metabolismo , Metilación , Ratones Endogámicos C57BL , Células-Madre Neurales/metabolismo , Neuronas/metabolismo , Factor de Transcripción 1 de la Leucemia de Células Pre-B/metabolismo , Unión Proteica , Estabilidad Proteica , Transporte de Proteínas , Receptores Citoplasmáticos y Nucleares/metabolismo , Transducción de Señal , Proteína Exportina 1RESUMEN
Pre-B-cell leukemia homeobox (PBX) and myeloid ecotropic viral integration site (MEIS) proteins control cell fate decisions in many physiological and pathophysiological contexts, but how these proteins function mechanistically remains poorly defined. Focusing on the first hours of neuronal differentiation of adult subventricular zone-derived stem/progenitor cells, we describe a sequence of events by which PBX-MEIS facilitates chromatin accessibility of transcriptionally inactive genes: In undifferentiated cells, PBX1 is bound to the H1-compacted promoter/proximal enhancer of the neuron-specific gene doublecortin (Dcx) Once differentiation is induced, MEIS associates with chromatin-bound PBX1, recruits PARP1/ARTD1, and initiates PARP1-mediated eviction of H1 from the chromatin fiber. These results for the first time link MEIS proteins to PARP-regulated chromatin dynamics and provide a mechanistic basis to explain the profound cellular changes elicited by these proteins.