MAFG-AS1/MAFG positive feedback loop contributes to cisplatin resistance in bladder urothelial carcinoma through antagonistic ferroptosis

• 作者: Liang Xiang Qinghai Zeng Jianye Liu Mengqing Xiao Dong He Qun Zhang Dan Xie Minhua Deng Yuxing Zhu Yan Liu Hao Bo Xiaoming Liu Ming Zhou Wei Xiong Yanhong Zhou Jianda Zhou Xiaohui Li Ke Cao
• 来源期刊: 科学通报（英文版）
• 年，卷（期）: 2021,（17）
• 所属期刊栏目: ARTICLES
• 页码范围: 1773-1788
• 页数: 16页
• 语种: 英文

摘要

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 fer-roptosis.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 indepen-dent 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 cis-platin through promoting ferroptosis,indicating the novel chemotherapy sensitivity biomarkers and therapeutic target for BUC.