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

Zsuzsanna Nagy, Janith A. Seneviratne, Maxwell Kanikevich, William Chang, Chelsea Mayoh, Pooja Venkat, Yanhua Du, Cizhong Jiang, Alice Salib, Jessica Koach, Daniel R. Carter, Rituparna Mittra, Tao Liu, Michael W. Parker, Belamy B. Cheung () and Glenn M. Marshall ()
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Zsuzsanna Nagy: Lowy Cancer Research Centre, UNSW
Janith A. Seneviratne: Lowy Cancer Research Centre, UNSW
Maxwell Kanikevich: Lowy Cancer Research Centre, UNSW
William Chang: Lowy Cancer Research Centre, UNSW
Chelsea Mayoh: Lowy Cancer Research Centre, UNSW
Pooja Venkat: Lowy Cancer Research Centre, UNSW
Yanhua Du: Tongji University
Cizhong Jiang: Tongji University
Alice Salib: Lowy Cancer Research Centre, UNSW
Jessica Koach: Lowy Cancer Research Centre, UNSW
Daniel R. Carter: Lowy Cancer Research Centre, UNSW
Rituparna Mittra: Lowy Cancer Research Centre, UNSW
Tao Liu: Lowy Cancer Research Centre, UNSW
Michael W. Parker: The University of Melbourne
Belamy B. Cheung: Lowy Cancer Research Centre, UNSW
Glenn M. Marshall: Lowy Cancer Research Centre, UNSW

Nature Communications, 2021, vol. 12, issue 1, 1-20

Abstract: Abstract To achieve the very high oncoprotein levels required to drive the malignant state cancer cells utilise the ubiquitin proteasome system to upregulate transcription factor levels. Here our analyses identify ALYREF, expressed from the most common genetic copy number variation in neuroblastoma, chromosome 17q21-ter gain as a key regulator of MYCN protein turnover. We show strong co-operativity between ALYREF and MYCN from transgenic models of neuroblastoma in vitro and in vivo. The two proteins form a nuclear coactivator complex which stimulates transcription of the ubiquitin specific peptidase 3, USP3. We show that increased USP3 levels reduce K-48- and K-63-linked ubiquitination of MYCN, thus driving up MYCN protein stability. In the MYCN-ALYREF-USP3 signal, ALYREF is required for MYCN effects on the malignant phenotype and that of USP3 on MYCN stability. This data defines a MYCN oncoprotein dependency state which provides a rationale for future pharmacological studies.

Date: 2021
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DOI: 10.1038/s41467-021-22143-x

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