Journal
CELL DEATH & DISEASE
Volume 12, Issue 11, Pages -Publisher
SPRINGERNATURE
DOI: 10.1038/s41419-021-04212-7
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Funding
- Guangdong gastrointestinal disease research center [2017B020209003]
- Natural Science Foundation of China [82003291, 82002593, 31701174]
- Outstanding Youth Development Scheme of Nanfang Hospital, Southern Medical University and Natural Science Foundation of Guangdong Province [2020A1515011283]
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This study found that EZH2 knockout colorectal cancer cells were more likely to survive under glucose deprivation conditions, and showed a negative correlation with GLS expression. This provides an explanation for the clinical tolerance of cancer cells to EZH2 inhibitors and suggests the potential of combining EZH2 inhibitors with glutamine metabolism inhibitors for cancer treatment.
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.
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