The Deubiquitinase USP28 Maintains the Expression of the Transcription Factor MYCN and Is Essential in Neuroblastoma Cells.

Neuroblastoma (NB) is one of the most common extracranial solid tumors in children. MYCN gene amplification is highly associated with poor prognosis in high-risk neuroblastoma patients. In non-MYCN-amplified high-risk NB patients, the expression of c-MYC (MYCC) and its target genes is highly elevated. USP28 as a deubiquitinase is known to regulate the stability of MYCC. We show here USP28 also regulates the stability of MYCN. Genetic depletion or pharmacologic inhibition of the deubiquitinase strongly destabilizes MYCN and stops the growth of neuroblastoma cells that overexpress MYCN. In addition, MYCC could be similarly destabilized in non-MYCN neuroblastoma cells by compromising USP28 function. Our results strongly suggest USP28 as a therapeutic target for neuroblastoma with or without MYCN amplification/overexpression.