LIN28B regulates transcription and potentiates MYCN-induced neuroblastoma through binding to ZNF143 at target gene promotors
Menée à l'aide de poissons-zèbres transgéniques, cette étude met en évidence un mécanisme par lequel la protéine LIN28B, en interagissant avec le facteur de transcription à doigt de zinc ZNF143 au niveau des promoteurs des gènes cibles, favorise le développement d'un neuroblastome induit par le proto-oncogène MYCN
LIN28B is well known as a RNA-binding protein and a suppressor of microRNA biogenesis by selectively blocking the processing of let-7 precursors. However, little is known about let-7–independent roles of LIN28B. Here, we show that LIN28B is recruited to active promoters by binding to the zinc-finger transcription factor ZNF143. LIN28B acts as a cofactor to upregulate expression of a subset of downstream target genes that are essential for neuroblastoma cell survival and migration. Our paper reveals an unexpected role of LIN28B in transcriptional regulation that is independent of let-7 during neuroblastoma pathogenesis.LIN28B is highly expressed in neuroblastoma and promotes tumorigenesis, at least, in part, through inhibition of let-7 microRNA biogenesis. Here, we report that overexpression of either wild-type (WT) LIN28B or a LIN28B mutant that is unable to inhibit let-7 processing increases the penetrance of MYCN-induced neuroblastoma, potentiates the invasion and migration of transformed sympathetic neuroblasts, and drives distant metastases in vivo. Genome-wide chromatin immunoprecipitation coupled with massively parallel DNA sequencing (ChIP-seq) and coimmunoprecipitation experiments show that LIN28B binds active gene promoters in neuroblastoma cells through protein–protein interaction with the sequence-specific zinc-finger transcription factor ZNF143 and activates the expression of downstream targets, including transcription factors forming the adrenergic core regulatory circuitry that controls the malignant cell state in neuroblastoma as well as GSK3B and L1CAM that are involved in neuronal cell adhesion and migration. These findings reveal an unexpected let-7–independent function of LIN28B in transcriptional regulation during neuroblastoma pathogenesis.