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

Hongming Song; Jihong Lu; Yining Zhang; Zhidong Lv; Yuhua Song; Wenqin Wang; Yaoyu Xu; Tiantian Bian; Yongmei Wang; Lei Zhang; Xiaohui Su; Dengfeng Li; Zhaohe Niu

doi:10.1016/j.jbc.2026.113242

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

J Biol Chem. 2026 Jun 9;302(8):113242. doi: 10.1016/j.jbc.2026.113242. Online ahead of print.

Authors

Hongming Song¹, Jihong Lu², Yining Zhang³, Zhidong Lv³, Yuhua Song³, Wenqin Wang⁴, Yaoyu Xu⁵, Tiantian Bian³, Yongmei Wang³, Lei Zhang³, Xiaohui Su³, Dengfeng Li⁶, Zhaohe Niu⁷

Affiliations

¹ Breast Disease Center, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, China. Electronic address: hongmingsong@qdu.edu.cn.
² Department of Breast Surgery, The First Hospital of China Medical University, Shenyang, Liaoning, China.
³ Breast Disease Center, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, China.
⁴ School of Health and Life Sciences, University of Health and Rehabilitation Sciences, Qingdao, Shandong, China.
⁵ College of Chemistry and Chemical Engineering, Anyang Normal University, Anyang, Henan, China.
⁶ Department of Breast and Thyroid Surgery, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China. Electronic address: 711ldf@tongji.edu.cn.
⁷ Breast Disease Center, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, China. Electronic address: nzh1974@126.com.

Abstract

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.

Keywords: FTO; VGLL4-STAT3 signaling; cancer progression; m6A modification; triple-negative breast cancer.