Phosphorylation of p62/Sqstm1 renders tumor cells drug tolerance and proliferation potency


Masaaki Komatsu;


p62/Sqstm1 is a multifunctional protein involved in cell survive, growth and death and degraded by autophagy. Phosphorylation of p62/Sqstm1 at Ser351 causes inactivation of Keap1, an adaptor of the Cul3-ubiquitin ligase complex responsible for degrading a transcription factor, Nrf2. The phosphorylated p62/Sqstm1 accumulates in autophagy-deficient mouse liver tumor and human hepatocellular carcinoma(HCC), which assists their growth depending on Nrf2-activation. However, the molecular mechanism how the p62-Keap1-Nrf2 axis provides tumor cells with proliferation potency remains unclear. Herein, we show unique glucose and glutamine metabolisms in autophagy-defective mouse livers and HCC cells harboring S351-phosphorylated p62/Sqstm1 and demonstrate their effects on anti-cancer drug tolerance as well as tumor growth.


p62/Sqstm1;;Keap1;;Nrf2;;Hepatocellular carcinoma;;Metabolomic analysis


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