Format

Send to

Choose Destination
Cancer Res. 2019 Sep 9. pii: canres.1112.2019. doi: 10.1158/0008-5472.CAN-19-1112. [Epub ahead of print]

Drugging MYCN oncogenic signalling through the MYCN-PA2G4 binding interface.

Author information

1
Molecular Carcinogenesis Program, Children's Cancer Institute Australia.
2
St Vincents Institute of Medical Research.
3
Molecular Carcinogenesis Program, Children's Cancer Institute Australia for Medical Research.
4
Molecular Carcinogenesis, Children's Cancer Institute Australia.
5
Department of Pharmacy and Biotechnology, University of Bologna.
6
Experimental Therapeutics, Children's Cancer Institute Australia.
7
Children's Cancer Institute, Lowy Cancer Research Centre, UNSW Sydney.
8
Histone Modification Group, Children's Cancer Institute Australia.
9
Personalised Medicine Program, Children's Cancer Institute Australia.
10
Medical Faculty, Institute of Molecular Medicine.
11
Institute of Molecular Medicine, Martin Luther University Halle-Wittenberg.
12
Department of Pediatric Intensive Care Medicine and Department of Oncology and Hematology, University of Cologne, Children's Hospital.
13
Department of Pediatric Oncology and Hematology, University Children's Hospital, and Center for Molecular Medicine Cologne (CMMC), University Children's Hospital of Cologne.
14
Department of Biochemistry and Molecular Biology, Mayo Clinic.
15
Pediatrics, University of California, San Francisco.
16
Molecular Diagnostics, Children's Cancer Institute.
17
Department of Biology, University of Bologna.
18
Structural Biology, St. Vincent's Institute of Medical Research - Victoria 3065, Australia.
19
Centre for Children's Cancer and Blood Disorders, Centre for Children's Cancer and Blood Disorders g.marshall@unsw.edu.au.

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). ChIP 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 modelling, surface plasmon resonance and mutagenesis studies, we mapped the MYCN-PA2G4 interaction site to a fourteen 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 cofactor in MYCN-driven neuroblastoma and highlight competitive inhibition of the PA2G4-MYCN protein binding as a novel therapeutic strategy in the disease.

Supplemental Content

Full text links

Icon for HighWire
Loading ...
Support Center