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N(6)-甲基腺苷甲基化调控的类 polo 样激酶 1 细胞周期平衡作为胰腺腺癌放疗的潜在靶点。

N(6)-methyladenosine methylation-regulated polo-like kinase 1 cell cycle homeostasis as a potential target of radiotherapy in pancreatic adenocarcinoma.

机构信息

Department of Radiation Oncology, Osaka University Graduate School of Medicine, Yamadaoka 2-2, Suita, Osaka, 565-0871, Japan.

Department of Medical Data Science, Center of Medical Innovation and Translational Research, Osaka University Graduate School of Medicine, Yamadaoka 2-2, Suita, Osaka, 565-0871, Japan.

出版信息

Sci Rep. 2022 Jun 30;12(1):11074. doi: 10.1038/s41598-022-15196-5.

DOI:10.1038/s41598-022-15196-5
PMID:35773310
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9246847/
Abstract

In pancreatic cancer, methyltransferase-like 3 (METTL3), a N(6)-methyladenosine (m6A) methyltransferase, has a favorable effect on tumors and is a risk factor for patients' prognosis. However, the details of what genes are regulated by METTL3 remain unknown. Several RNAs are methylated, and what genes are favored in pancreatic cancer remains unclear. By epitranscriptomic analysis, we report that polo-like kinase 1 (PLK1) is an important hub gene defining patient prognosis in pancreatic cancer and that RNA methylation is involved in regulating its cell cycle-specific expression. We found that insulin like growth factor 2 mRNA binding protein 2 (IGF2BP2) binds to m6A of PLK1 3' untranslated region and is involved in upregulating PLK1 expression and that demethylation of this site activates the ataxia telangiectasia and Rad3-related protein pathway by replicating stress and increasing mitotic catastrophe, resulting in increased radiosensitivity. This suggests that PLK1 methylation is essential for cell cycle maintenance in pancreatic cancer and is a new therapeutic target.

摘要

在胰腺癌中，甲基转移酶样 3（METTL3）作为 N（6）-甲基腺苷（m6A）甲基转移酶，对肿瘤有促进作用，是患者预后的危险因素。然而，METTL3 调控的具体基因仍不清楚。有几种 RNA 发生甲基化，在胰腺癌中哪些基因受到调控尚不清楚。通过表转录组学分析，我们报告称，丝氨酸/苏氨酸激酶 polo 样激酶 1（PLK1）是一个重要的枢纽基因，可定义胰腺癌患者的预后，并且 RNA 甲基化参与调节其细胞周期特异性表达。我们发现胰岛素样生长因子 2 mRNA 结合蛋白 2（IGF2BP2）结合到 PLK1 的 3'非翻译区的 m6A 上，并参与上调 PLK1 的表达，而该位点的去甲基化通过复制应激和增加有丝分裂灾难激活共济失调毛细血管扩张和 Rad3 相关蛋白通路，导致放射敏感性增加。这表明 PLK1 甲基化对于维持胰腺癌的细胞周期至关重要，是一个新的治疗靶点。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f135/9246847/5ebdac17edd3/41598_2022_15196_Fig7_HTML.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f135/9246847/9220f0b3a825/41598_2022_15196_Fig3_HTML.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f135/9246847/f1db122dff13/41598_2022_15196_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f135/9246847/5ebdac17edd3/41598_2022_15196_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f135/9246847/808ade800441/41598_2022_15196_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f135/9246847/da39b10102ef/41598_2022_15196_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f135/9246847/9220f0b3a825/41598_2022_15196_Fig3_HTML.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f135/9246847/f1db122dff13/41598_2022_15196_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f135/9246847/5ebdac17edd3/41598_2022_15196_Fig7_HTML.jpg

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