A novel feedback regulation loop of METTL11A–MAFG–NPL4 promotes bladder cancer cell proliferation and tumor progression

• DOI: 10.1096/fj.202402830r
• Publication Date: 2025-04-04T08:01:50Z
• Authors: Bao‐Sai Lu; Kai‐Long Liu; Yue‐Wei Yin; Yan‐Ping Zhang; Jin‐Chun Qi; Chen‐Ming Zhao; Ya‐Lin Niu; Ping‐Ying Guo; Wei Li

AbstractAbnormal regulation of gene expression results in the malignant proliferation of bladder cancer (BC) cells. We previously demonstrated that NPL4 upregulation promotes BC progression; however, its regulatory and functional mechanisms on downstream genes in BC remain unknown. Transcriptome sequencing and reverse transcription–quantitative polymerase chain reaction were used to identify and confirm METTL11A as a downstream gene of NPL4. Protein interactions were detected through co‐immunoprecipitation assays. Cell growth and tumor progression were assessed in vitro and in vivo using colony formation and MTS assays as well as xenograft animal models. Chromatin immunoprecipitation and luciferase activity assays were performed to investigate gene transcription regulation. We identified METTL11A as a downstream gene of NPL4, with its upregulation linked to poor outcomes in BC patients. METTL11A facilitates NPL4‐regulated BC cell proliferation by promoting cyclin D1 expression. METTL11A enhances MAFG expression and contributes to METTL11A‐mediated cell proliferation. Mechanistically, METTL11A interacts with MAFG, preventing its degradation through K6 methylation modification. MAFG and NRF2 bind to the promoter region of NPL4, promoting its transcription. Thus, the METTL11A–MAFG–NPL4 axis forms a positive feedback loop, promoting BC cell proliferation and tumor progression. Targeted inhibition of this regulatory loop could offer a novel therapeutic approach for BC.