Yifan Luo, Zhengjiang Qian, Guandou Yuan, Shuai Yang, Wei Gong, Yangyang Zhai, Wenting Dai, Jiawei An, Yuchu Liu, Qiuyue Jiang, Yang Su, Ning Ren, Min Guan, Yongfeng Yang, Feng Rao, 何坤炎, Keqiang Ye
Abstract Hyperglycemia and its related diseases, such as diabetes, dramatically accelerate cancer progression. However, the underlying mechanisms remain poorly understood, and the development of anticancer therapies based on them has largely stalled. Transcription factor CCAAT/enhancer binding protein beta (C/EBPβ) is strongly associated with glucose metabolic disorders and cancer progression. Here we show that C/EBPβ is significantly upregulated in hepatocellular carcinoma patients previously diagnosed with diabetes. Notably, high glucose activates C/EBPβ transcription via ROS-dependent PERK-eIF2α-ATF4 signaling. Intriguingly, the LAP isoforms of C/EBPβ, but not the LIP isoform, upregulate key glycolytic effectors (GLUT1 and LDHA) and the oncoprotein HRAS, thereby promoting glycolysis and proliferation in liver cancer cells. Remarkably, hyperglycemia-accelerated hepatocellular glycometabolism and hepatocellular carcinoma progression in male mice are greatly prevented by hepatocyte-specific C/EBPβ deletion or Lucicebtide (ST101) treatment, a clinical phase-II C/EBPβ inhibitory peptide. Moreover, human C/EBPβ isoform LAP1 mimics the effect of hyperglycemia to boost hepatocellular glycometabolism and accelerate hepatocellular carcinoma progression. Thus, C/EBPβ is a critical regulator and potential therapeutic target for glucose-fueled cancer progression.