<i>FTO</i>-induced <i>APOE</i> promotes the malignant progression of pancreatic neuroendocrine neoplasms through <i>FASN</i>-mediated lipid metabolism
N6-methyladenosine (m6A) is considered the most prevalent RNA epigenetic regulator in cancer. FTO, an m6A demethylase, has been implicated in contributing to the progression of various cancers by up-regulating the expression of multiple oncogenes. However, studies exploring its impact on lipid metabolism in cancer, especially in pNENs, remain scarce. In this study, we demonstrated that FTO was up-regulated in pNENs and played a critical role in tumor growth and lipid metabolism. Mechanistically, we discovered that FTO over-expression increased the expression of APOE in an m6A-IGF2BP2-dependent manner, leading to dysregulation of lipid metabolism. Furthermore, we found APOE could activate the PI3K/AKT/mTOR signaling pathway, thereby enhancing lipid metabolism and proliferative capabilities, by orchestrating the state of FASN ubiquitination. In conclusion, our study reveals the FTO/IGF2BP2/APOE/FASN/mTOR axis as a mechanism underlying aberrant m6A modification in lipid metabolism and provides new insights into the molecular basis for developing therapeutic strategies for pNENs treatment.
Authors
- Lingyi Chen (ORCID: https://orcid.org/0000-0002-3695-3407)
- Xiaoting Shi (ORCID: https://orcid.org/0000-0002-5256-0646)
- Qiyun Tang (ORCID: https://orcid.org/0000-0002-8354-5406)
- Yanling Xu (ORCID: https://orcid.org/0000-0001-7572-4204)
- Bingyang Xue
- Danyang Gu (ORCID: https://orcid.org/0000-0001-9464-877X)
- Jinhao Chen (ORCID: https://orcid.org/0009-0006-3272-0135)
- Mujie Ye (ORCID: https://orcid.org/0000-0002-5363-2752)
- Lijun Yan (ORCID: https://orcid.org/0000-0002-5993-273X)
- Jian’an Bai (ORCID: https://orcid.org/0000-0001-7822-7297)
- Ye Tian (ORCID: https://orcid.org/0000-0002-1833-1807)
- Yán Wāng (ORCID: https://orcid.org/0000-0002-2940-3300)
- Lin Xu (ORCID: https://orcid.org/0000-0002-6889-0279)
- Chunhua Hu (ORCID: https://orcid.org/0000-0002-6487-4204)
- Feiyu Lu (ORCID: https://orcid.org/0000-0002-3688-9759)
- Ping Yu (ORCID: https://orcid.org/0000-0002-6096-1933)
Institutions
- Chinese Academy of Medical Sciences & Peking Union Medical College (CN)
- Peking Union Medical College Hospital (CN)
- Yili Friendship Hospital (CN)
- Nanjing Medical University (CN)
Publication Details
- Journal
- International Journal of Biological Sciences
- Published
- 2025-01-27
- DOI
- https://doi.org/10.7150/ijbs.103428
- Citations
- 12
- Primary Topic
- Cancer, Lipids, and Metabolism
- Type
- article
- Field-Weighted Citation Impact
- 11.23
Funders
- National Natural Science Foundation of China
- China Postdoctoral Science Foundation