Department of Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China; Sino-German Laboratory of Personalized Medicine for Pancreatic Cancer, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
TCM Regulating Metabolic Diseases Key Laboratory of Sichuan Province, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, 610000, China.
Cancer Lett. 2023 Jul 1;565:216222. doi: 10.1016/j.canlet.2023.216222. Epub 2023 May 19.
In eukaryotes, N-methyladenosine (m6A) is the most prevalent epigenetic alteration. Methyltransferase-like 3 (METTL3) is a key player in the control of m6A, although its function in pancreatic cancer is incompletely understood. In this study, we examined the role that METTL3 plays in pancreatic cancer cell proliferation and stemness. We discovered that in pancreatic cancer cells, METTL3-mediated m6A alterations regulate ID2 as a downstream target. The stability of ID2 mRNA was decreased and m6A modification was effectively eliminated by METTL3 knockdown in pancreatic cancer cells. We also demonstrate that m6a-YTHDF2 is necessary for the METTL3-mediated stabilization of ID2 mRNA. Additionally, we show that ID2 controls the stemness molecules NANOG and SOX2 via the PI3K-AKT pathway to support pancreatic cancer growth and stemness maintenance. Our data suggest that METTL3 may post-transcriptionally upregulate ID2 expression in an m6A-YTHDF2-dependent manner to further promote the stabilization of ID2 mRNA, which may be a new target for pancreatic cancer treatment.
在真核生物中，N6-甲基腺苷（m6A）是最普遍的表观遗传修饰。甲基转移酶样蛋白 3（METTL3）是控制 m6A 的关键因子，尽管其在胰腺癌中的功能尚未完全阐明。在本研究中，我们研究了 METTL3 在胰腺癌细胞增殖和干性中的作用。我们发现，在胰腺癌细胞中，METTL3 介导的 m6A 改变作为下游靶点调节 ID2。METTL3 敲低可降低 ID2 mRNA 的稳定性并有效消除 m6A 修饰。我们还证明 m6A-YTHDF2 对于 METTL3 介导的 ID2 mRNA 稳定是必需的。此外，我们表明 ID2 通过 PI3K-AKT 通路控制 NANOG 和 SOX2 等干性分子，以支持胰腺癌细胞生长和干性维持。我们的数据表明，METTL3 可能以 m6A-YTHDF2 依赖的方式转录后上调 ID2 的表达，从而进一步促进 ID2 mRNA 的稳定，这可能是胰腺癌治疗的新靶点。
Cell Commun Signal. 2025-5-30
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