Koach, Jessica, Holien, Jessica K., Massudi, Hassina, Carter, Daniel R., Ciampa, Olivia C., Herath, Mika, Lim, Taylor, Seneviratne, Janith A., Milazzo, Giorgio ORCID: 0000-0002-1930-4763, Murray, Jayne E., McCarroll, Joshua A., Liu, Bing, Mayoh, Chelsea, Keenan, Bryce, Stevenson, Brendan W., Gorman, Michael A., Bell, Jessica L., Doughty, Larissa, Huettelmaier, Stefan, Oberthuer, Andre, Fischer, Matthias, Gifford, Andrew J., Liu, Tao ORCID: 0000-0001-6244-7316, Zhang, Xiaoling, Zhu, Shizhen, Gustafson, W. Clay, Haber, Michelle, Norris, Murray D., Fletcher, Jamie I., Perini, Giovanni, Parker, Michael W., Cheung, Belamy B. and Marshall, Glenn M. (2019). Drugging MYCN Oncogenic Signaling through the MYCN-PA2G4 Binding Interface. Cancer Res., 79 (21). S. 5652 - 5668. PHILADELPHIA: AMER ASSOC CANCER RESEARCH. ISSN 1538-7445

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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 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. Significance: Competitive chemical inhibition of the PA2G4-MYCN protein interface provides a basis for drug design of small molecules targeting MYC and MYCN-binding partners in malignancies driven by MYC family oncoproteins.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Koach, JessicaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Holien, Jessica K.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Massudi, HassinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Carter, Daniel R.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ciampa, Olivia C.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Herath, MikaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lim, TaylorUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Seneviratne, Janith A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Milazzo, GiorgioUNSPECIFIEDorcid.org/0000-0002-1930-4763UNSPECIFIED
Murray, Jayne E.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
McCarroll, Joshua A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Liu, BingUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mayoh, ChelseaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Keenan, BryceUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Stevenson, Brendan W.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gorman, Michael A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bell, Jessica L.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Doughty, LarissaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Huettelmaier, StefanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Oberthuer, AndreUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Fischer, MatthiasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gifford, Andrew J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Liu, TaoUNSPECIFIEDorcid.org/0000-0001-6244-7316UNSPECIFIED
Zhang, XiaolingUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Zhu, ShizhenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gustafson, W. ClayUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Haber, MichelleUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Norris, Murray D.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Fletcher, Jamie I.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Perini, GiovanniUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Parker, Michael W.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Cheung, Belamy B.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Marshall, Glenn M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-129390
DOI: 10.1158/0008-5472.CAN-19-1112
Journal or Publication Title: Cancer Res.
Volume: 79
Number: 21
Page Range: S. 5652 - 5668
Date: 2019
Publisher: AMER ASSOC CANCER RESEARCH
Place of Publication: PHILADELPHIA
ISSN: 1538-7445
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
HISTONE DEACETYLASE 2; N-MYC; TUMOR-SUPPRESSOR; EBP1 ISOFORMS; PROTEIN EBP1; LONG ISOFORM; NEUROBLASTOMA; EXPRESSION; KINASE; AURORAMultiple languages
OncologyMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/12939

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