Though promoting ferroptosis can reduce cisplatin resistance in tumor cells,ferroptosis and cisplatin resistance in bladder urothelial carcinoma(BUC)following long non-coding RNAs(lncRNAs)is largely unknown.Here,we fo...Though promoting ferroptosis can reduce cisplatin resistance in tumor cells,ferroptosis and cisplatin resistance in bladder urothelial carcinoma(BUC)following long non-coding RNAs(lncRNAs)is largely unknown.Here,we found the highly expressed lncRNA MAF transcription factor G antisense RNA 1(MAFG-AS1)in BUC,and its inhibition increased the sensitivity of BUC cells to cisplatin by promoting ferroptosis.Mechanically,binding to iron chaperone poly(rC)-binding protein 2(PCBP2)facilitated the recruitments of MAFG-AS1 to deubiquitinase ubiquitin carboxyl-terminal hydrolase isozyme L5(UCHL5),thus stabilizing PCBP2 protein itself.Then PCBP2 was confirmed to interact with ferroportin 1(FPN1),an iron export protein,leading to inhibition of ferroptosis.Moreover,the expression of MAFG-AS1 was regulated by the transcriptional factor MAFG.Interestingly,MAFG-AS1 stimulated MAFG transcription by recruiting histone acetyltransferase p300(EP300)to promote the histone 3 at lysine 27(H3K27ac)at genomic locus of MAFG,forming a MAFG-AS1/MAFG positive feedback loop.In patient samples,higher expression of MAFG-AS1 and MAFG in BUC tissues was significantly correlated with T status and N status,such that MAFG-AS1,MAFG,and the combination of the two were independent prognostic indicators and chemotherapy sensitivity predictive biomarkers for BUC patients.These findings suggest that inhibition of MAFG-AS1 and MAFG can increase the sensitivity of BUC cells to cisplatin through promoting ferroptosis,indicating the novel chemotherapy sensitivity biomarkers and therapeutic target for BUC.展开更多
基金This work was supported by the National Natural Science Foundation of China(81874137)the Outstanding Youth Foundation of Hunan Province(2018JJ1047)+4 种基金the Huxiang Young Talent Project(2016RS3022)the Hunan Province Science and Technology Talent Promotion Project(2019TJ-Q10)the Project of Scientific Research Plan of Health and Family Planning Commission of Hunan Province(c20180476)the Fundamental Research Funds for the Central South University(2018zzts938)the Wisdom Accumulation and Talent Cultivation Project of the Third Xiangya Hosipital of Central South University(ZC060001 and YX202007).
文摘Though promoting ferroptosis can reduce cisplatin resistance in tumor cells,ferroptosis and cisplatin resistance in bladder urothelial carcinoma(BUC)following long non-coding RNAs(lncRNAs)is largely unknown.Here,we found the highly expressed lncRNA MAF transcription factor G antisense RNA 1(MAFG-AS1)in BUC,and its inhibition increased the sensitivity of BUC cells to cisplatin by promoting ferroptosis.Mechanically,binding to iron chaperone poly(rC)-binding protein 2(PCBP2)facilitated the recruitments of MAFG-AS1 to deubiquitinase ubiquitin carboxyl-terminal hydrolase isozyme L5(UCHL5),thus stabilizing PCBP2 protein itself.Then PCBP2 was confirmed to interact with ferroportin 1(FPN1),an iron export protein,leading to inhibition of ferroptosis.Moreover,the expression of MAFG-AS1 was regulated by the transcriptional factor MAFG.Interestingly,MAFG-AS1 stimulated MAFG transcription by recruiting histone acetyltransferase p300(EP300)to promote the histone 3 at lysine 27(H3K27ac)at genomic locus of MAFG,forming a MAFG-AS1/MAFG positive feedback loop.In patient samples,higher expression of MAFG-AS1 and MAFG in BUC tissues was significantly correlated with T status and N status,such that MAFG-AS1,MAFG,and the combination of the two were independent prognostic indicators and chemotherapy sensitivity predictive biomarkers for BUC patients.These findings suggest that inhibition of MAFG-AS1 and MAFG can increase the sensitivity of BUC cells to cisplatin through promoting ferroptosis,indicating the novel chemotherapy sensitivity biomarkers and therapeutic target for BUC.
