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
Autism spectrum disorder（ASD） refers to a group of childhood neurodevelopmental disorders with polygenic etiology. The expression of many genes implicated in ASD is tightly regulated by various factors including mic...Autism spectrum disorder（ASD） refers to a group of childhood neurodevelopmental disorders with polygenic etiology. The expression of many genes implicated in ASD is tightly regulated by various factors including microRNAs（miRNAs）, a class of noncoding RNAs 22 nucleotides in length that function to suppress translation by pairing with ‘miRNA recognition elements’（MREs） present in the 30untranslated region（30UTR） of target mRNAs. This emphasizes the role played by miRNAs in regulating neurogenesis, brain development and differentiation and hence any perturbations in this regulatory mechanism might affect these processes as well. Recently, single nucleotide polymorphisms（SNPs） present within 30UTRs of mRNAs have been shown to modulate existing MREs or even create new MREs. Therefore, we hypothesized that SNPs perturbing miRNA-mediated gene regulation might lead to aberrant expression of autism-implicated genes, thus resulting in disease predisposition or pathogenesis in at least a subpopulation of ASD individuals. We developed a systematic computational pipeline that integrates data from well-established databases. By following a stringent selection criterion, we identified 9 MRE-modulating SNPs and another 12 MRE-creating SNPs in the 30UTR of autism-implicated genes. These high-confidence candidate SNPs may play roles in ASD and hence would be valuable for further functional validation.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.
基金supported by a grant from the Depart-ment of Biotechnology,New Delhi,India to AKM(Grant No.BT/PR10023/AGR/36/27/2007)supported by a research fellowship from the Council of Scientific and Indus-trial Research,New Delhi
文摘Autism spectrum disorder（ASD） refers to a group of childhood neurodevelopmental disorders with polygenic etiology. The expression of many genes implicated in ASD is tightly regulated by various factors including microRNAs（miRNAs）, a class of noncoding RNAs 22 nucleotides in length that function to suppress translation by pairing with ‘miRNA recognition elements’（MREs） present in the 30untranslated region（30UTR） of target mRNAs. This emphasizes the role played by miRNAs in regulating neurogenesis, brain development and differentiation and hence any perturbations in this regulatory mechanism might affect these processes as well. Recently, single nucleotide polymorphisms（SNPs） present within 30UTRs of mRNAs have been shown to modulate existing MREs or even create new MREs. Therefore, we hypothesized that SNPs perturbing miRNA-mediated gene regulation might lead to aberrant expression of autism-implicated genes, thus resulting in disease predisposition or pathogenesis in at least a subpopulation of ASD individuals. We developed a systematic computational pipeline that integrates data from well-established databases. By following a stringent selection criterion, we identified 9 MRE-modulating SNPs and another 12 MRE-creating SNPs in the 30UTR of autism-implicated genes. These high-confidence candidate SNPs may play roles in ASD and hence would be valuable for further functional validation.
