Journal article

Drugging MYCN Oncogenic Signaling through the MYCN-PA2G4 Binding Interface

Jessica Koach, Jessica K Holien, Hassina Massudi, Daniel R Carter, Olivia C Ciampa, Mika Herath, Taylor Lim, Janith A Seneviratne, Giorgio Milazzo, Jayne E Murray, Joshua A McCarroll, Bing Liu, Chelsea Mayoh, Bryce Keenan, Brendan W Stevenson, Michael A Gorman, Jessica L Bell, Larissa Doughty, Stefan Huettelmaier, Andre Oberthuer Show all

Cancer Research | AMER ASSOC CANCER RESEARCH | Published : 2019

Abstract

MYCN is a major driver for the childhood cancer, neuroblastoma, however, there are no inhibitors of this target. Enhanced MYCN protein stability is a key component of MYCN oncogenesis and is maintained by multiple feedforward expression loops involving MYCN transactivation target genes. Here, we reveal the oncogenic role of a novel MYCN target and binding protein, proliferation-associated 2AG4 (PA2G4). Chromatin immunoprecipitation studies demonstrated that MYCN occupies the PA2G4 gene promoter, stimulating transcription. Direct binding of PA2G4 to MYCN protein blocked proteolysis of MYCN and enhanced colony formation in a MYCN-dependent manner. Using molecular modeling, surface plasmon reso..

View full abstract

Grants

Awarded by National Health and Medical Research Council (NHMRC) Australia


Awarded by Cancer Institute NSW


Awarded by Cancer Council NSW


Awarded by NHMRC



Funding Acknowledgements

This work was supported by Program Grants (to G.M. Marshall, M.D. Norris, and Michelle Haber) from the National Health and Medical Research Council (NHMRC) Australia (APP1016699), Cancer Institute NSW (10/TPG/1-13), Cancer Council NSW (PG-11-06), and an Australia Postgraduate Research Award, UNSW Sydney, Australia (to J. Koach). This work was also supported by NHMRC Project grant APP1125171 and Neuroblastoma Australia (to G.M. Marshall and B.B. Cheung); Project grant APP571073; Senior Principal Research Fellowship to M.W. Parker, Cure Cancer Australia Foundation, Leukemia Foundation, and 5-point Foundation (Postdoctoral Fellowships to J.K. Holien). Infrastructure support from the NHMRC Independent Research Institutes Infrastructure Support Schemeand the Victorian State Government Operational Infrastructure Support Program to St Vincent's Institute is gratefully acknowl-edged. The authors thank the Sydney Children's Tumour Bank Network for providing samples and related clinical information for this study.