Reciprocal Induction of MDM2 and MYCN in Neural and Neuroendocrine Cancers

Hung N Tran; Hardeep P Singh; Wenxuan Guo; Linda Cambier; Luke Riggan; Gregory M Shackleford; Matthew E Thornton; Brendan H Grubbs; Anat Erdreich-Epstein; Dong-Lai Qi; David Cobrinik

doi:10.3389/fonc.2020.563156

Reciprocal Induction of MDM2 and MYCN in Neural and Neuroendocrine Cancers

Front Oncol. 2020 Dec 23:10:563156. doi: 10.3389/fonc.2020.563156. eCollection 2020.

Authors

Hung N Tran¹, Hardeep P Singh^{2

3

4}, Wenxuan Guo^{2

3

5}, Linda Cambier^{2

3}, Luke Riggan², Gregory M Shackleford^{3

6}, Matthew E Thornton⁷, Brendan H Grubbs⁷, Anat Erdreich-Epstein^{1

3

8}, Dong-Lai Qi^{2

3

9}, David Cobrinik^{2

3

4

10}

Affiliations

¹ Division of Hematology/Oncology, Children's Hospital Los Angeles, Los Angeles, CA, United States.
² The Vision Center, Department of Surgery, Children's Hospital Los Angeles, Los Angeles, CA, United States.
³ The Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, CA, United States.
⁴ Department of Ophthalmology and Roski Eye Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States.
⁵ Program in Biomedical and Biological Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States.
⁶ Department of Radiology, Children's Hospital Los Angeles, Los Angeles, CA, United States.
⁷ Department of Obstetrics and Gynecology, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States.
⁸ Departments of Pediatrics and Pathology, Children's Hospital Los Angeles and Keck School of Medicine, and Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States.
⁹ Medicine and Pharmacy Research Center, Binzhou Medical University, Yantai, China.
¹⁰ Department of Biochemistry and Molecular Medicine and Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States.

Abstract

MYC family oncoproteins MYC, MYCN, and MYCL are deregulated in diverse cancers and via diverse mechanisms. Recent studies established a novel form of MYCN regulation in MYCN-overexpressing retinoblastoma and neuroblastoma cells in which the MDM2 oncoprotein promotes MYCN translation and MYCN-dependent proliferation via a p53-independent mechanism. However, it is unclear if MDM2 also promotes expression of other MYC family members and has similar effects in other cancers. Conversely, MYCN has been shown to induce MDM2 expression in neuroblastoma cells, yet it is unclear if MYC shares this ability, if MYC family proteins upregulate MDM2 in other malignancies, and if this regulation occurs during tumorigenesis as well as in cancer cell lines. Here, we report that intrinsically high MDM2 expression is required for high-level expression of MYCN, but not for expression of MYC, in retinoblastoma, neuroblastoma, small cell lung cancer, and medulloblastoma cells. Conversely, ectopic overexpression of MYC as well as MYCN induced high-level MDM2 expression and gave rise to rapidly proliferating and MDM2-dependent cone-precursor-derived masses in a cultured retinoblastoma genesis model. These findings reveal a highly specific collaboration between the MDM2 and MYCN oncoproteins and demonstrate the origin of their oncogenic positive feedback circuit within a normal neuronal tissue.

Keywords: MDM2; MYC; MYCN; medulloblastoma; neuroblastoma; retinoblastoma; small cell lung cancer.

Grants and funding

R01 CA137124/CA/NCI NIH HHS/United States