GSE150303 An ALYREF-MYCN coactivator complex drives neuroblastoma tumorigenesis through effects on USP3 and MYCN stability

Contributors : Zsuzsanna Nagy ; Yanhua Du ; Janith A Seneviratne ; Cizhong Jiang ; Glenn M MarshallSeries Type : Genome binding/occupancy profiling by high throughput sequencingOrganism : Homo sapiensTo achieve the very high oncoprotein levels required to drive the malignant state, cancer cells utilise the ubiquitin proteasome system to regulate proteins involved in growth signalling pathways. Here we identify a transcriptional coactivator, ALYREF, expressed from the most common genetic copy number variation in childhood neuroblastoma, chromosome 17q21-ter gain. We show strong co-operativity between ALYREF and MYCN from transgenic models of neuroblastoma in vitro and in vivo. MYCN induced ALYREF transcription, and the two proteins formed a nuclear coactivator complex which stimulated transcription of the ubiquitin specific peptidase 3, USP3. We found that increased USP3 levels markedly reduced K-48- and K-63-linked ubiquitination of MYCN, thus driving up MYCN protein stability. In the MYCN-ALYREF-USP3 signal, ALYREF was required for MYCN effects on the malignant phenotype in vitro and that of USP3 on MYCN stability. Our data define a novel MYCN oncoprotein dependency state which provides rationale for future pharmacological studies.
Source: GEO: Gene Expression Omnibus - Category: Genetics & Stem Cells Tags: Genome binding/occupancy profiling by high throughput sequencing Homo sapiens Source Type: research