Reciprocal Induction of MDM2 and MYCN in Neural and Neuroendocrine Cancers.

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

doi:10.3389/fonc.2020.563156

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.

Highlights

MYC family proteins MYC, MYCN, and MYCL have important roles in development, homeostasis, and oncogenesis [1, 2]
To assess whether MDM2 has a general role in regulation of MYC family proteins, we queried the effects of MDM2 knockdown in a series of neuroendocrine cancer cell lines
We focused on cancers that have high-level expression of MYCN and/or MYC in different instances, including retinoblastoma cells that co-express MYCN and MYC (RB176), neuroblastoma cells that highly express either MYCN (SK-N-BE[1]) or MYC (CHLA255, SH-SY5Y), small cell lung carcinoma (SCLC) cells that highly express either MYCN (H69, H526) or MYC (H211, H82), and SHHlike (DAOY, UW228-2) and Group 3 (D283, D341, D425) medulloblastoma lines for which only MYC-expressing lines are known (Table 1)

Summary

Introduction

MYC family proteins MYC, MYCN, and MYCL have important roles in development, homeostasis, and oncogenesis [1, 2]. The different MYC family members have distinct expression patterns [2, 3] yet share the ability to promote growth of the tissues in which they are expressed [4]. The contributions of particular MYC family proteins in different cancers parallel their developmental expression, with deregulation of MYC in diverse hematologic and solid tumors, deregulation of MYCN mainly in neuroendocrine and neuronal tumors, and deregulation of MYCL in small cell lung carcinoma (SCLC) [5]. Different SCLCs have amplified MYC, MYCN, or MYCL [7], and different medulloblastoma subgroups overexpress either MYC or MYCN but not both [8, 9]. The largely mutually exclusive overexpression of MYC family members is consistent with their having similar oncogenic effects

Methods

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Conclusion