Myc promotes glutaminolysis in human neuroblastoma through direct activation of glutaminase 2.

Daibiao Xiao,Ping Ren,Hudan Liu,Ming Yue,Hexiu Su,Ruijuan Xiu,Yufeng Hu,Guoliang Qing

doi:10.18632/oncotarget.5821

Abstract

Deamidation of glutamine to glutamate by glutaminase 1 (GLS1, also called GLS) and GLS2 is an essential step in both glutaminolysis and glutathione (GSH) biosynthesis. However, mechanisms whereby cancer cells regulate glutamine catabolism remains largely unknown. We report here that N-Myc, an essential Myc family member, promotes conversion of glutamine to glutamate in MYCN-amplified neuroblastoma cells by directly activating GLS2, but not GLS1, transcription. Abrogation of GLS2 function profoundly inhibited glutaminolysis, which resulted in feedback inhibition of aerobic glycolysis likely due to thioredoxin-interacting protein (TXNIP) activation, dramatically decreasing cell proliferation and survival in vitro and in vivo. Moreover, elevated GLS2 expression is significantly elevated in MYCN-amplified neuroblastomas in comparison with non-amplified ones, correlating with unfavorable patient survival. In aggregate, these results reveal a novel mechanism deciphering context-dependent regulation of metabolic heterogeneities, uncovering a previously unsuspected link between Myc, GLS2 and tumor metabolism.

Highlights

Neuroblastoma is one of the most frequent solid tumors detected in childhood
Using an antibody recognizing both isoforms of GLS1, we only detected the 53 KD protein band of GAC isoform in neuroblastoma cell lysates (Figure 1D), which was further confirmed by shRNA depletion in additional neuroblastoma cell lines (Supplementary Figure S1), demonstrating that GAC is the predominant GLS1 isoform expressed in human neuroblastoma cells
Our results reveal that metabolic control of N-Myc induced neuroblastomas differs from that of c-Myc transformed Burkitt’s lymphomas, with one of the checkpoints being differential regulation of GLS1 versus GLS2 activation

Summary

Introduction

Neuroblastoma is one of the most frequent solid tumors detected in childhood. Risk factors indicative of poor prognosis include age >18 months at diagnosis, unfavorable histological grade and MYCN amplification [1]. Amplification of the MYCN gene, which occurs in approximately 25% of human neuroblastomas overall and 40% of high-risk cases, remains the most important and reliable oncogenic marker [1]. MYCN amplification is consistently associated with high levels of N-Myc protein, which contribute to aggressive phenotypes by regulating and/or cooperating with other oncogenic pathways [1, 2]. Increased glycolysis alone is insufficient to meet the total metabolic demands of proliferating cancer cells. Elevated glutaminolysis is another hallmark of cancer [6,7,8,9,10,11]

Methods

Results

Conclusion