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

Schematic diagram of MAFG-AS1/MAFG positive feedback loop antagonizes ferroptosis in BUC. MAFG-AS1 stimulates MAFG transcription by promoting H3K27ac at genomic loci of MAFG through recruiting acetylase EP300. MAFG binds to the MAFG-AS1 gene promoter to induce MAFG-AS1 expression, forming a positive feedback loop. MAFG-AS1 could recruit deubiquitinase UCHL5 to stabilize the expression of PCBP2 protein. Then PCBP2 interacts with transferrin 1 (FPN1) and transports iron out of the cells, leading inhibition of ferroptosis and cisplatin resistance in BUC cells. 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. [Display omitted] 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. [ABSTRACT FROM AUTHOR]