Ras Downstream Effector GGCT Alleviates Oncogenic Stress

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

doi:10.1016/j.isci.2019.07.036

Ras Downstream Effector GGCT Alleviates Oncogenic Stress

iScience. 2019 Sep 27:19:256-266. doi: 10.1016/j.isci.2019.07.036. Epub 2019 Jul 26.

Authors

Zaoke He¹, Shixiang Wang¹, Yuanyuan Shao², Jing Zhang¹, Xiaolin Wu², Yuxing Chen², Junhao Hu³, Feng Zhang⁴, Xue-Song Liu⁵

Affiliations

¹ School of Life Science and Technology, ShanghaiTech University, Shanghai 201203, China; Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai, China; University of Chinese Academy of Sciences, Beijing, China.
² School of Life Science and Technology, ShanghaiTech University, Shanghai 201203, China.
³ Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China.
⁴ Core Facility, Department of Clinical Laboratory, Quzhou People's Hospital, Quzhou, Zhejiang, China.
⁵ School of Life Science and Technology, ShanghaiTech University, Shanghai 201203, China. Electronic address: liuxs@shanghaitech.edu.cn.

Abstract

How 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.

Keywords: Biological Sciences; Cancer; Cell Biology.