Ras Downstream Effector GGCT Alleviates Oncogenic Stress.

Zaoke He,Junhao Hu,Jing Zhang,Xue-Song Liu,Shixiang Wang,Yuxing Chen,Feng Zhang,Xiaolin Wu,Yuanyuan Shao

doi:10.1016/j.isci.2019.07.036

Abstract

SummaryHow cells adapt to oncogenic transformation-associated cellular stress and become fully transformed is still unknown. Here we identified a novel GGCT-regulated glutathione (GSH)-reactive oxygen species (ROS) metabolic pathway in oncogenic stress alleviation. We identified GGCT as a target of oncogenic Ras and that it is required for oncogenic Ras-induced primary mouse cell proliferation and transformation and in vivo lung cancer formation in the LSL-Kras G12D mouse model. However, GGCT deficiency is compatible with normal mouse development, suggesting that GGCT can be a cancer-specific therapeutic target. Genetically amplified GGCT locus further supports the oncogenic driving function of GGCT. In summary, our study not only identifies an oncogenic function of GGCT but also identifies a novel regulator of GSH metabolism, with implications for further understanding of oncogenic stress and cancer treatment.

Highlights

Oncogenic transformation in primary somatic cells always leads to cellular stresses, which function as a failsafe mechanism to prevent cancer formation (Luo et al, 2009)
Recent cancer genomics efforts, such as The Cancer Genome Atlas (TCGA), enable us to systematically study the genetic alterations in cancer, and many novel oncogenes or tumor suppressors have been identified in this way (Kandoth et al, 2013; Zack et al, 2013)
We focused on the copy number alterations of human lung adenocarcinoma (LUAD), and observed that the short arm of chromosome 7 (7p) is among the top amplified chromosome fragments based on several independent studies (Balsara and Testa, 2002; Lu et al, 2011; Ni et al, 2013; Weir et al, 2007; Wu et al, 2015) (Figure S1A)

Summary

Introduction

Oncogenic transformation in primary somatic cells always leads to cellular stresses, which function as a failsafe mechanism to prevent cancer formation (Luo et al, 2009). We identified a novel oncogenic Ras downstream target GGCT, and further characterized GGCT function using mouse models, cancer genomics, and cell biochemical approaches. G-Glutamyl cyclotransferase catalyzes the following reaction: g-glutamyl-amino acid / 5-oxoproline + amino acid. C7orf is not the only protein showing this enzyme activity in mammalian cells (Chi et al, 2014). This enzyme was supposed to participate in glutathione (GSH) homeostasis. G-glutamyl cyclotransferase cleaves the g-glutamyl-amino acid to give 5-oxoproline and amino acid (Meister, 1974). The function of GGCT (C7orf24) in GSH homeostasis is still unknown. The function of g-glutamyl cyclotransferase enzyme activity in cancer is unknown; association between this enzyme activity and human cancer has not been reported

Methods

Results

Discussion

Conclusion