LIN28B regulates transcription and potentiates MYCN-induced neuroblastoma through binding to ZNF143 at target gene promotors.

Abstract

LIN28B is highly expressed in neuroblastoma and promotes tumorigenesis, at least, in part, through inhibition of <i>let-7</i> microRNA biogenesis. Here, we report that overexpression of either wild-type (WT) LIN28B or a LIN28B mutant that is unable to inhibit <i>let-7</i> 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 <i>GSK3B</i> and <i>L1CAM</i> that are involved in neuronal cell adhesion and migration. These findings reveal an unexpected <i>let-7</i>-independent function of LIN28B in transcriptional regulation during neuroblastoma pathogenesis.