Abstract：
In eukaryotes, N6-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.
摘要：
在真核生物中,N6-甲基腺苷(m6A)是最普遍的表观遗传改变。甲基转移酶样3（METTL3）是控制m6A的关键角色，尽管其在胰腺癌中的功能尚未完全了解。在这项研究中,我们研究了METTL3在胰腺癌细胞增殖和干细胞性中的作用.我们发现在胰腺癌细胞中，METTL3介导的m6A改变将ID2调节为下游靶标。在胰腺癌细胞中，通过METTL3敲低，ID2mRNA的稳定性降低，m6A修饰被有效消除。我们还证明m6a-YTHDF2对于METTL3介导的ID2mRNA的稳定是必需的。此外,我们发现ID2通过PI3K-AKT通路控制干性分子NANOG和SOX2,以支持胰腺癌的生长和干性维持.我们的数据表明，METTL3可能以m6A-YTHDF2依赖性方式在转录后上调ID2表达，以进一步促进ID2mRNA的稳定，这可能是胰腺癌治疗的新靶点。
