HNRNPC-Mediated m6A Methylation of ZNF146 Promotes Triple-Negative Breast Cancer Progression through Regulating MRPL21

Background Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer. The aim of this study was to investigate the expression pattern of ZNF146 in TNBC and explore its role and mechanism in promoting TNBC growth and metastasis. Methods The expression pattern and prognostic value of ZNF146 in breast cancer and normal breast tissue were analyzed using data from TCGA and CPTAC. Lentiviral vectors were used to overexpress or knockdown ZNF146 in TNBC cell lines, which was verified by real-time PCR and western Blot. Functional assays including MTT, EdU, and transwell were performed to investigate the effects of ZNF146 on TNBC cell proliferation, migration, and invasion. Xenograft and tail vein metastasis mouse models were used to evaluate the role of ZNF146 in vivo. The regulatory mechanism of ZNF146 was explored through RNA-Seq, RIP, ChIP, and dual luciferase reporter assays. Results ZNF146 was highly expressed in TNBC and correlated with poor patient survival. Overexpression of ZNF146 promoted TNBC cell proliferation and metastasis both in vitro and in vivo, while knockdown exerted the opposite effect. RNA-Seq analysis revealed MRPL21 as a potential downstream target of ZNF146, which was proved to be an oncogene. ChIP and dual luciferase reporter assays demonstrated that ZNF146 directly binds to the MRPL21 promoter and regulates its expression. MRPL21 overexpression mimicked ZNF146 effects, while its knockdown inhibited TNBC cell proliferation and migration. In addition, HNRNPC, an m6A reader protein, regulates ZNF146 expression in an m6A-dependent manner. Conclusions Our study identifies ZNF146 as a novel oncogenic driver in TNBC, which promotes cancer progression by upregulating MRPL21 expression in an HNRNPC-mediated m6A-dependent manner. These findings provide new insights into the molecular mechanisms underlying TNBC progression and identify potential therapeutic targets.