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Int J Biol Sci 2024; 20(3):916-936. doi:10.7150/ijbs.87203 This issue Cite

Research Paper

The inhibition of YTHDF3/m⁶A/LRP6 reprograms fatty acid metabolism and suppresses lymph node metastasis in cervical cancer

Sheng Zhong^1,2#, Quanwei Guo^3#, Xiaona Chen^1,2#, Xiaomin Luo^1,2#, Yufei Long^1,2, Tuotuo Chong^1,2, Ming Ye⁴, Hui He⁵, Anwei Lu⁶, Keyi Ao^1,2, Minuo Yin⁶, Aimin Xu⁷, Xin Li^1,2✉, Yi Hao^8✉, Xia Guo^1,2✉

1. Shenzhen Key Laboratory of Viral Oncology; Department of Science and Innovation, Shenzhen Hospital, Southern Medical University, Shenzhen, China.
2. The Third School of Clinical Medicine, Southern Medical University Guangzhou, China.
3. Department of Thoracic Surgery, Shenzhen Hospital, Southern Medical University, Shenzhen, China.
4. Department of Pathology, Affiliated Tumor Hospital of Xinjiang Medical University, Urumqi, China.
5. Department of Pathology, Shenzhen Hospital, The University of Hong Kong, Shenzhen, China.
6. Department of Obstetrics and Gynecology, Shenzhen Hospital of Southern Medical University, Shenzhen, China.
7. Department of Medicine, University of Hongkong, Hongkong, China.
8. Department of Ultrasound, South China Hospital of Shenzhen University, Shenzhen, China.
^#These authors contributed equally to the research.

✉ Corresponding authors: Xia Guo, myshow0504edu.cn, Shenzhen Key Laboratory of Viral Oncology; Department of Science and Innovation, Shenzhen Hospital, Southern Medical University. No 1333 Xinhu Road, Shenzhen 518100, China; Phone/Fax: +86 075523360150. Yi Hao, haoyi0320szcom, Department of Ultrasound, South China Hospital of Shenzhen University, Shenzhen 518000, China; Phone/Fax: +86 075589698999. Xin Li, xinli268com, Shenzhen Key Laboratory of Viral Oncology; Shenzhen Hospital, Southern Medical University. No 1333 Xinhu Road, Shenzhen 518100, China; Phone/Fax: +86 13711475900. More

Abstract

The lipid synthesis of fatty acid (FA) represents a significant hallmark in the occurrence and progression of malignant tumor, which are associated with lymph node (LN) metastasis. Elucidation of the molecular mechanisms underlying LN metastasis could provide therapeutic strategies for cervical cancer (CCa). N6-Methyladenosine (m⁶A), the most prevalent and abundant RNA modification, exerts specific regulatory control over a series of oncogene expressions. This study demonstrated a clinical correlation between the upregulation of the m⁶A reader YTHDF3 and LN metastasis, thereby contributing to poor overall survival probability (OS) among CCa patients. The mechanistic investigation revealed that SREBF1 transcriptionally activated YTHDF3 expression by binding to its promoter. Functional experiments demonstrated that the upregulation of YTHDF3 significantly enhanced the in vitro proliferative, migratory, and invasive capacities of CCa cells, while also promoting lymphangiogenesis and facilitating LN metastasis in vivo. Mechanistically, the upregulation of LRP6 through YTHDF3-mediated m⁶A modification resulted in increased expression of FASN and ACC1, leading to both lipolysis of lipid droplets and synthesis of free fatty acid. Ultimately, this promoted fatty acid metabolism and enhanced LN metastasis by activating the LRP6-YAP-VEGF-C axis, which could induce lymphangiogenesis in CCa. Our study highlighted that YTHDF3 can serve as a promising therapeutic target and predictive biomarker for CCa patients with LN metastasis.

Keywords: cervical cancer, YTHDF3, m⁶A, lymph node metastasis, LRP6, fatty acid metabolism

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