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

LIN28B is highly expressed in neuroblastoma and promotes tumorigenesis, at least, in part, through inhibition of let-7 micro-RNA 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 M...

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Published inProceedings of the National Academy of Sciences - PNAS Vol. 117; no. 28; pp. 16516 - 16526
Main Authors Tao, Ting, Shi, Hui, Mariani, Luca, Abraham, Brian J., Durbin, Adam D., Zimmerman, Mark W., Powers, John T., Missios, Pavlos, Ross, Kenneth N., Perez-Atayde, Antonio R., Bulyk, Martha L., Young, Richard A., Daley, George Q., Look, A. Thomas
Format Journal Article
LanguageEnglish
Published Washington National Academy of Sciences 14.07.2020
Subjects
Amino acid sequence
Biological Sciences
Cell adhesion
Cell adhesion & migration
Chromatin
Circuits
Deoxyribonucleic acid
DNA
DNA sequencing
Gene regulation
Genomes
Immunoprecipitation
Metastases
miRNA
Neuroblastoma
Neuroblasts
Pathogenesis
Proteins
Ribonucleic acid
RNA
Transcription factors
Tumorigenesis
Zinc finger proteins
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Summary:LIN28B is highly expressed in neuroblastoma and promotes tumorigenesis, at least, in part, through inhibition of let-7 micro-RNA 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.
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Edited by Louis M. Staudt, National Cancer Institute, Bethesda, MD, and approved May 31, 2020 (received for review January 19, 2020)
1T.T. and H.S. contributed equally to this work.
Author contributions: T.T., H.S., M.L.B., R.A.Y., G.Q.D., and A.T.L. designed research; T.T., H.S., A.D.D., M.W.Z., J.T.P., and P.M. performed research; L.M. contributed new reagents/analytic tools; T.T., H.S., L.M., B.J.A., A.D.D., M.W.Z., J.T.P., P.M., K.N.R., A.R.P.-A., M.L.B., R.A.Y., G.Q.D., and A.T.L. analyzed data; and T.T. and A.T.L. wrote the paper.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.1922692117