通过MYCN-PA2G4结合界面对MYCN致癌信号进行药物治疗。,Cancer Research

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通过MYCN-PA2G4结合界面对MYCN致癌信号进行药物治疗。
Cancer Research ( IF 12.5 ) Pub Date : 2019-09-09 , DOI: 10.1158/0008-5472.can-19-1112
Jessica Koach _{1,

2} , Jessica K Holien ₃ , Hassina Massudi ₁ , Daniel R Carter _{1,

4,

5} , Olivia C Ciampa ₁ , Mika Herath ₁ , Taylor Lim ₁ , Janith A Seneviratne ₁ , Giorgio Milazzo ₆ , Jayne E Murray ₁ , Joshua A McCarroll _{1,

7} , Bing Liu ₁ , Chelsea Mayoh ₁ , Bryce Keenan ₁ , Brendan W Stevenson ₃ , Michael A Gorman _{3,

8} , Jessica L Bell ₉ , Larissa Doughty _{3,

8} , Stefan Hüttelmaier ₉ , Andre Oberthuer _{10,

11} , Matthias Fischer _{10,

12} , Andrew J Gifford _{1,

13} , Tao Liu ₁ , Xiaoling Zhang ₁₄ , Shizhen Zhu ₁₄ , W Clay Gustafson ₂ , Michelle Haber ₁ , Murray D Norris ₁ , Jamie I Fletcher ₁ , Giovanni Perini ₆ , Michael W Parker _{3,

8} , Belamy B Cheung _{1,

4,

15} , Glenn M Marshall _{1,

4,

16}

Affiliation

Children's Cancer Institute Australia for Medical Research, Lowy Cancer Research Centre, UNSW Sydney, Kensington, New South Wales, Australia.
Department of Pediatrics, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, California.
ACRF Rational Drug Discovery Centre, St. Vincent's Institute of Medical Research, Fitzroy, Victoria, Australia.
School of Women's & Children's Health, UNSW Sydney, Randwick New South Wales, Australia.
School of Biomedical Engineering, University of Technology Sydney, Australia.
Department of Pharmacy and Biotechnology, University of Bologna, Bologna, Italy.
Australian Centre for NanoMedicine, ARC Centre for Excellence in Convergent Bio-Nano Science and Technology, UNSW, Australia.
Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, Victoria, Australia.
The Section for Molecular Cell Biology, Institute of Molecular Medicine, Martin Luther University of Halle, Halle, Germany.
Department of Pediatric Oncology and Hematology, Children's Hospital, University of Cologne, Cologne, Germany.
Department of Neonatology and Pediatric Intensive Care Medicine, Children's Hospital, University of Cologne, Cologne, Germany.
Max Planck Institute for Metabolism Research, Cologne, Germany.
Department of Anatomical Pathology, Prince of Wales Hospital, Randwick, New South Wales, Australia.
Department of Biochemistry and Molecular Biology, Cancer Center and Center for Individualized Medicine, Mayo Clinic, Rochester, Minnesota.
School of Life Sciences and Technology, Tongji University, Shanghai, China.
Kids Cancer Centre, Sydney Children's Hospital, Randwick, New South Wales, Australia.

MYCN是导致儿童期癌症，神经母细胞瘤的主要驱动力，但是，没有针对该靶标的抑制剂。MYCN蛋白稳定性的增强是MYCN肿瘤发生的关键组成部分，并通过涉及MYCN反式激活靶基因的多个前馈表达环得以维持。在这里，我们揭示了新型MYCN靶标和结合蛋白，增殖相关2AG4（PA2G4）的致癌作用。染色质的免疫沉淀研究表明，MYCN占据了PA2G4基因启动子，刺激了转录。PA2G4与MYCN蛋白的直接结合可阻止MYCN的蛋白水解，并以MYCN依赖性的方式增强菌落的形成。使用分子建模，表面等离子体共振和诱变研究，我们将MYCN-PA2G4相互作用位点映射到14个氨基酸的MYCN序列和PA2G4的表面缝隙。竞争性化学抑制MYCN-PA2G4蛋白-蛋白界面在体内对神经母细胞瘤的肿瘤发生具有有效的抑制作用。治疗的肿瘤显示MYCN和PA2G4水平降低。我们的发现表明，PA2G4作为MYCN驱动的神经母细胞瘤中辅助因子的关键作用，并突出显示了PA2G4-MYCN蛋白结合的竞争性抑制，是该疾病的一种新型治疗策略。意义：竞争性化学抑制PA2G4-MYCN蛋白界面为靶向MYC和MYCN结合伴侣的小分子在MYC家族癌蛋白驱动的恶性肿瘤中的药物设计提供了基础。我们的发现表明，PA2G4作为MYCN驱动的神经母细胞瘤中辅助因子的关键作用，并突出显示了PA2G4-MYCN蛋白结合的竞争性抑制，是该疾病的一种新型治疗策略。意义：竞争性化学抑制PA2G4-MYCN蛋白界面为靶向MYC和MYCN结合伴侣的小分子在MYC家族癌蛋白驱动的恶性肿瘤中的药物设计提供了基础。我们的发现表明，PA2G4作为MYCN驱动的神经母细胞瘤中辅助因子的关键作用，并突出显示了PA2G4-MYCN蛋白结合的竞争性抑制，是该疾病的一种新型治疗策略。意义：竞争性化学抑制PA2G4-MYCN蛋白界面为靶向MYC和MYCN结合伴侣的小分子在MYC家族癌蛋白驱动的恶性肿瘤中的药物设计提供了基础。

"点击查看英文标题和摘要"

Drugging MYCN Oncogenic Signaling through the MYCN-PA2G4 Binding Interface.

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.

更新日期：2019-11-01

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