2. Academic Validation
  3. Tumor-suppressive function of EZH2 is through inhibiting glutaminase

Tumor-suppressive function of EZH2 is through inhibiting glutaminase

  • Cell Death Dis. 2021 Oct 20;12(11):975. doi: 10.1038/s41419-021-04212-7.
Yongfeng Liu  # 1,  Cheng-E Tu  # 2,  Xuxue Guo  # 2,  Changjie Wu 2,  Chuncai Gu 2,  Qiuhua Lai 2,  Yuxin Fang 2,  Junqi Huang 3,  Zhizhang Wang 4,  Aimin Li 5,  Side Liu 6
Affiliations

Affiliations

  • 1 Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China. lyf3433@163.com.
  • 2 Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China.
  • 3 Laboratory for Regenerative Medicine, Ministry of Education, College of Life Science and Technology, Jinan University, Guangzhou, 510632, China.
  • 4 Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China. wangzz89@smu.edu.cn.
  • 5 Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China. lam0725@163.com.
  • 6 Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China. sideliu@smu.edu.cn.
  • # Contributed equally.
PMID: 34671029 DOI: 10.1038/s41419-021-04212-7
Abstract

Tumors can use metabolic reprogramming to survive nutrient stress. Epigenetic regulators play a critical role in metabolic adaptation. Here we screened a sgRNA library to identify epigenetic regulators responsible for the vulnerability of colorectal Cancer (CRC) cells to glucose deprivation and found that more EZH2-knockout cells survived glucose deprivation. Then, we showed that EZH2 expression was significantly downregulated in response to glucose deprivation in a glucose-sensitive CRC cell line, and EZH2-knockdown cells were more resistant to glucose deprivation. Mechanistically, EZH2 deficiency upregulated the expression of Glutaminase (GLS) and promoted the production of glutamate, which in turn led to increased synthesis of intracellular glutathione (GSH) and eventually attenuated the Reactive Oxygen Species (ROS)-mediated cell death induced by glucose deprivation. Although EZH2 functioned as an oncogene in Cancer progression and EZH2 knockout abolished colorectal Cancer development in a mouse model, here we revealed a mechanistic link between EZH2 and metabolic reprogramming via the direct regulation of GLS expression and observed a negative correlation between EZH2 and GLS expression in colorectal Cancer tissues. These findings further confirmed the importance of heterogeneity, provided an explanation for the clinical tolerance of Cancer cells to EZH2 inhibitors from the perspective of metabolism, and proposed the possibility of combining EZH2 inhibitors and glutamine metabolism inhibitors for the treatment of Cancer.

Figures
Products