Chemotherapy is currently the mainstay of systemic management for triple-negative breast cancer(TNBC),but chemoresistance significantly impacts patient outcomes.Our research indicates that Doxorubicin(Dox)-resistant T...Chemotherapy is currently the mainstay of systemic management for triple-negative breast cancer(TNBC),but chemoresistance significantly impacts patient outcomes.Our research indicates that Doxorubicin(Dox)-resistant TNBC cells exhibit increased glycolysis and ATP generation compared to their parental cells,with this metabolic shift contributing to chemoresistance.We discovered that ALKBH3,an m^(1)A demethylase enzyme,is crucial in regulating the enhanced glycolysis in Doxresistant TNBC cells.Knocking down ALKBH3 reduced ATP generation,glucose consumption,and lactate production,implicating its involvement in mediating glycolysis.Further investigation revealed that aldolase A(ALDOA),a key enzyme in glycolysis,is a downstream target of ALKBH3.ALKBH3 regulates ALDOA mRNA stability through m^(1)A demethylation at the 30-untranslated region(30UTR).This methylation negatively affects ALDOA mRNA stability by recruiting the YTHDF2/PAN2ePAN3 complex,leading to mRNA degradation.The ALKBH3/ALDOA axis promotes Dox resistance both in vitro and in vivo.Clinical analysis demonstrated that ALKBH3 and ALDOA are upregulated in breast cancer tissues,and higher expression of these proteins is associated with reduced overall survival in TNBC patients.Our study highlights the role of the ALKBH3/ALDOA axis in contributing to Dox resistance in TNBC cells through regulation of ALDOA mRNA stability and glycolysis.展开更多
基金funded by the Research Project of TCM Bureau of Guangdong Province(20231324,China)the Special Fund of Foshan Climbing Peak Plan(2020B018,China)+1 种基金the Basic and Applied Basic Research Foundation of Guangdong Province(Grant No.2022A1515140091,China)the Natural Science Foundation of Guangdong Province(2023A1515030291,China).
文摘Chemotherapy is currently the mainstay of systemic management for triple-negative breast cancer(TNBC),but chemoresistance significantly impacts patient outcomes.Our research indicates that Doxorubicin(Dox)-resistant TNBC cells exhibit increased glycolysis and ATP generation compared to their parental cells,with this metabolic shift contributing to chemoresistance.We discovered that ALKBH3,an m^(1)A demethylase enzyme,is crucial in regulating the enhanced glycolysis in Doxresistant TNBC cells.Knocking down ALKBH3 reduced ATP generation,glucose consumption,and lactate production,implicating its involvement in mediating glycolysis.Further investigation revealed that aldolase A(ALDOA),a key enzyme in glycolysis,is a downstream target of ALKBH3.ALKBH3 regulates ALDOA mRNA stability through m^(1)A demethylation at the 30-untranslated region(30UTR).This methylation negatively affects ALDOA mRNA stability by recruiting the YTHDF2/PAN2ePAN3 complex,leading to mRNA degradation.The ALKBH3/ALDOA axis promotes Dox resistance both in vitro and in vivo.Clinical analysis demonstrated that ALKBH3 and ALDOA are upregulated in breast cancer tissues,and higher expression of these proteins is associated with reduced overall survival in TNBC patients.Our study highlights the role of the ALKBH3/ALDOA axis in contributing to Dox resistance in TNBC cells through regulation of ALDOA mRNA stability and glycolysis.
