Resistance to ferroptosis,a form of regulated cell death caused by disruptions in iron ion and intracellular redox homeostasis,is closely related to tumorigenesis and tumor drug resistance;therefore,targeting ferropto...Resistance to ferroptosis,a form of regulated cell death caused by disruptions in iron ion and intracellular redox homeostasis,is closely related to tumorigenesis and tumor drug resistance;therefore,targeting ferroptosis-related pathways has garnered attention as a potential antitumor therapeutic strategy.However,the molecular mechanisms underlying ferroptosis resistance in tumor cells remain unknown.Zinc-finger estrogen receptor interaction clone 6(ZER6)consists of two isoforms with distinct N-termini,p52-ZER6 and p71-ZER6.ZER6 is upregulated in tumors and promotes tumorigenic potential;however,whether ZER6 is involved in tumor cell ferroptosis resistance remains unknown.Herein,we identified p52-ZER6 as a novel regulator of tumor cell ferroptosis resistance.p52-ZER6 promotes the transcriptional activity of DAZAP1,an RNA-binding protein.DAZAP1,in turn,enhances the stability of SLC7A11 mRNA by binding to its 30-UTR region,thereby increasing SLC7A11 expression and cellular glutathione levels.This subsequently reduces lipid peroxide accumulation and enhances tumor cell ferroptosis resistance,eventually promoting tumorigenic potential.These findings reveal a new function of p52-ZER6 in regulating SLC7A11 mRNA stability via DAZAP1,ultimately leading to ferroptosis resistance and tumorigenic potential.Additionally,we also suggest targeting p52-ZER6 as a potential strategy to promote the efficacy of ferroptosis-based antitumor therapies.展开更多
基金supported by grants from the National Natural Science Foundation of China(82372655,82173029,32270778,and 32070715)the Natural Science Foundation of Chongqing(CSTB2022NSCQ-MSX0611 and CSTB2022NSCQ-MSX0612,China).
文摘Resistance to ferroptosis,a form of regulated cell death caused by disruptions in iron ion and intracellular redox homeostasis,is closely related to tumorigenesis and tumor drug resistance;therefore,targeting ferroptosis-related pathways has garnered attention as a potential antitumor therapeutic strategy.However,the molecular mechanisms underlying ferroptosis resistance in tumor cells remain unknown.Zinc-finger estrogen receptor interaction clone 6(ZER6)consists of two isoforms with distinct N-termini,p52-ZER6 and p71-ZER6.ZER6 is upregulated in tumors and promotes tumorigenic potential;however,whether ZER6 is involved in tumor cell ferroptosis resistance remains unknown.Herein,we identified p52-ZER6 as a novel regulator of tumor cell ferroptosis resistance.p52-ZER6 promotes the transcriptional activity of DAZAP1,an RNA-binding protein.DAZAP1,in turn,enhances the stability of SLC7A11 mRNA by binding to its 30-UTR region,thereby increasing SLC7A11 expression and cellular glutathione levels.This subsequently reduces lipid peroxide accumulation and enhances tumor cell ferroptosis resistance,eventually promoting tumorigenic potential.These findings reveal a new function of p52-ZER6 in regulating SLC7A11 mRNA stability via DAZAP1,ultimately leading to ferroptosis resistance and tumorigenic potential.Additionally,we also suggest targeting p52-ZER6 as a potential strategy to promote the efficacy of ferroptosis-based antitumor therapies.
