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

Author

Listed:
  • Zsuzsanna Nagy

    (Lowy Cancer Research Centre, UNSW
    UNSW Sydney)

  • 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
    UNSW Sydney)

  • 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
    UNSW Sydney
    University of Technology)

  • Rituparna Mittra

    (Lowy Cancer Research Centre, UNSW)

  • Tao Liu

    (Lowy Cancer Research Centre, UNSW)

  • Michael W. Parker

    (The University of Melbourne
    St. Vincent’s Institute of Medical Research)

  • Belamy B. Cheung

    (Lowy Cancer Research Centre, UNSW
    UNSW Sydney
    Tongji University)

  • Glenn M. Marshall

    (Lowy Cancer Research Centre, UNSW
    UNSW Sydney
    Kids Cancer Centre, Sydney Children’s Hospital)

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.

Suggested Citation

  • 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 Mitt, 2021. "An ALYREF-MYCN coactivator complex drives neuroblastoma tumorigenesis through effects on USP3 and MYCN stability," Nature Communications, Nature, vol. 12(1), pages 1-20, December.
  • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-22143-x
    DOI: 10.1038/s41467-021-22143-x
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