USP44 Overexpression Drives a MYC-Like Gene Expression Program in Neuroblastoma through Epigenetic Reprogramming.

Autor:	Ekstrom TL; Mayo Clinic Graduate School of Biomedical Sciences, Rochester, Minnesota.; Robert Bosch Center for Tumor Diseases, Stuttgart, Germany., Hussain S; Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, Minnesota.; Department of Family Medicine, Mayo Clinic, Rochester, Minnesota., Bedekovics T; Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, Minnesota., Ali A; Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, Minnesota., Paolini L; Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, Minnesota.; Department of Pediatrics, University of Milano-Bicocca, San Gerardo Hospital, Monza, Italy., Mahmood H; Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, Minnesota., Rosok RM; Robert Bosch Center for Tumor Diseases, Stuttgart, Germany., Koster J; Department of CEMM, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands., Johnsen SA; Robert Bosch Center for Tumor Diseases, Stuttgart, Germany., Galardy PJ; Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, Minnesota.; Division of Pediatric Hematology-Oncology, Mayo Clinic, Rochester, Minnesota.
Jazyk:	angličtina
Zdroj:	Molecular cancer research : MCR [Mol Cancer Res] 2024 Sep 04; Vol. 22 (9), pp. 812-825.
DOI:	10.1158/1541-7786.MCR-23-0454
Abstrakt:	Neuroblastoma is an embryonic cancer that contributes disproportionately to death in young children. Sequencing data have uncovered few recurrently mutated genes in this cancer, although epigenetic pathways have been implicated in disease pathogenesis. We used an expression-based computational screen that examined the impact of deubiquitinating enzymes on patient survival to identify potential new targets. We identified the histone H2B deubiquitinating enzyme USP44 as the enzyme with the greatest impact on survival in patients with neuroblastoma. High levels of USP44 significantly correlate with metastatic disease, unfavorable histology, advanced patient age, and MYCN amplification. The subset of patients with tumors expressing high levels of USP44 had significantly worse survival, including those with tumors lacking MYCN amplification. We showed experimentally that USP44 regulates neuroblastoma cell proliferation, migration, invasion, and neuronal development. Depletion of the histone H2B ubiquitin ligase subunit RNF20 resulted in similar findings, strongly implicating this histone mark as the target of USP44 activity in this disease. Integration of transcriptome and epigenome in analyses demonstrates a distinct set of genes that are regulated by USP44, including those in Hallmark MYC target genes in both murine embryonic fibroblasts and the SH-SY5Y neuroblastoma cell line. We conclude that USP44 is a novel epigenetic regulator that promotes aggressive features and may be a novel target in neuroblastoma. Implications: This study identifies a new genetic marker of aggressive neuroblastoma and identifies the mechanisms by which its overactivity contributes to the pathophysiology of this disease. (©2024 The Authors; Published by the American Association for Cancer Research.)
Databáze:	MEDLINE
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