FTO promotes cancer progression by regulating VGLL4 m6A levels to activate STAT3 signaling in triple-negative breast cancer

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Triple-negative breast cancer (TNBC) is a highly aggressive malignancy with poor prognosis and high mortality rates. Recent studies have highlighted the critical role of N6-methyladenosine (m6A) modification in cancer progression, yet the specific function of the m6A regulatory factor FTO in TNBC remains unclear. In this study, the expression of FTO in clinical samples was obtained from the GEO dataset, and correlation analysis between FTO expression and patient clinicopathological parameters was conducted. Functional assays, including MTT, colony formation, wound healing, transwell experiments, and in vivo tumor formation assay, were conducted to investigate the effect of FTO on the cellular behaviors of TNBC. qRT-PCR, immunohistochemistry (IHC), and Western blotting (WB) were conducted to examine the expression levels of FTO in TNBC, transcriptome sequencing, M6A-RNA immunoprecipitation (MeRIP), RNA immunoprecipitation (RIP), and RNA stability assays were employed to investigate the underlying mechanisms regulated by FTO. We confirmed that FTO is highly expressed in TNBC tissues. Furthermore, high FTO expression was associated with worse patient prognosis in TNBC. Functional assays demonstrated that FTO overexpression promotes TNBC cell proliferation, migration. In vivo studies demonstrated that overexpression of FTO promotes tumor growth in TNBC cells. Mechanistically, VGLL4 was identified as the target gene for FTO-mediated m6A modifcation. Our findings reveal that FTO drives TNBC progression by modifying the m6A level of VGLL4, leading to the activation of the STAT3 signaling pathway. In summary, these findings reveal the role of FTO-mediated m6A demethylation in TNBC and indicate potential therapeutic strategies for this aggressive disease.

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