Therapeutic targeting of the USP2-E2F4 axis inhibits autophagic machinery essential for zinc homeostasis in cancer progression

Wenjing Xiao, Jianqun Wang, Xiaojing Wang, Shuang Cai, Yanhua Guo, Lin Ye, Dan Li, Anpei Hu, Shikai Jin, Boling Yuan, Yi Zhou, Qilan Li, Qiangsong Tong & Liduan Zheng
Macroautophagy/autophagy is a conserved cellular process associated with tumorigenesis and aggressiveness, while mechanisms regulating expression of autophagic machinery genes in cancers still remain elusive. Herein, we identified E2F4 (E2F transcription factor 4) as a novel transcriptional activator of cytoprotective autophagy crucial for zinc homeostasis in cancer cells. Gain- and loss-of-function studies showed that E2F4 promoted autophagy in a cell cycle-dependent manner, resulting in facilitated degradation of MT (metallothionein) proteins, elevated distribution of Zn2+ within autophagosomes,...
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