@article{a699092c889e4ddba6c4eeaeb8fcaad1,
title = "Drugging MYCN oncogenic signaling through the MYCN-PA2G4 binding interface",
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, proliferationassociated 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 MYCNdependent manner. Using molecular modeling, surface plasmon resonance, and mutagenesis studies, we mapped the MYCN-PA2G4 interaction site to a 14 amino acid MYCN sequence and a surface crevice of PA2G4. Competitive chemical inhibition of the MYCN-PA2G4 protein-protein interface had potent inhibitory effects on neuroblastoma tumorigenesis in vivo. Treated tumors showed reduced levels of both MYCN and PA2G4. Our findings demonstrate a critical role for PA2G4 as a cofactor in MYCN-driven neuroblastoma and highlight competitive inhibition of the PA2G4-MYCN protein binding as a novel therapeutic strategy in the disease.",
author = "Jessica Koach and Holien, {Jessica K.} and Hassina Massudi and Carter, {Daniel R.} and Ciampa, {Olivia C.} and Mika Herath and Taylor Lim and Seneviratne, {Janith A.} and Giorgio Milazzo and Murray, {Jayne E.} and McCarroll, {Joshua A.} and Bing Liu and Chelsea Mayoh and Bryce Keenan and Stevenson, {Brendan W.} and Gorman, {Michael A.} and Bell, {Jessica L.} and Larissa Doughty and Stefan H{\"u}ttelmaier and Andre Oberthuer and Matthias Fischer and Gifford, {Andrew J.} and Tao Liu and Xiaoling Zhang and Shizhen Zhu and Gustafson, {W. Clay} and Michelle Haber and Norris, {Murray D.} and Fletcher, {Jamie I.} and Giovanni Perini and Parker, {Michael W.} and Cheung, {Belamy B.} and Marshall, {Glenn M.}",
note = "Funding Information: (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 Scheme and the Victorian State Government Operational Infrastructure Support Program to St Vincent's Institute is gratefully acknowl- Funding Information: 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 Funding Information: 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 Scheme and the Victorian State Government Operational Infrastructure Support Program to St Vincent's Institute is gratefully acknowledged. The authors thank the Sydney Children's Tumour Bank Network for providing samples and related clinical information for this study. Publisher Copyright: {\textcopyright} 2019 American Association for Cancer Research.",
year = "2019",
month = nov,
day = "1",
doi = "10.1158/0008-5472.CAN-19-1112",
language = "English (US)",
volume = "79",
pages = "5652--5667",
journal = "Cancer research",
issn = "0008-5472",
number = "21",
}