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RNA 去甲基酶 ALKBH5 通过 mA-IGF2BP2 依赖性的转录后激活 NFE2L2/NRF2 来调节下咽鳞癌细胞铁死亡。

RNA demethylase ALKBH5 regulates hypopharyngeal squamous cell carcinoma ferroptosis by posttranscriptionally activating NFE2L2/NRF2 in an m A-IGF2BP2-dependent manner.

机构信息

Department of Otolaryngology Head and Neck Surgery, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.

Laboratory of Cancer Biology, Institute of Clinical Science, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.

出版信息

J Clin Lab Anal. 2022 Jul;36(7):e24514. doi: 10.1002/jcla.24514. Epub 2022 Jun 11.

DOI:10.1002/jcla.24514
PMID:35689537
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9279968/
Abstract

BACKGROUND

Having emerged as the most abundant posttranscriptional internal mRNA modification in eukaryotes, N6-methyladenosine (m A) has attracted tremendous scientific interest in recent years. However, the functional importance of the m A methylation machinery in ferroptosis regulation in hypopharyngeal squamous cell carcinoma (HPSCC) remains unclear.

METHODS

We herein performed bioinformatic analysis, cell biological analyses, transcriptome-wide m A sequencing (m A-seq, MeRIP-seq), RNA sequencing (RNA-seq), and RNA immunoprecipitation sequencing (RIP-seq), followed by m A dot blot, MeRIP-qPCR, RIP-qPCR, and dual-luciferase reporter assays.

RESULTS

The results revealed that ALKBH5-mediated m A demethylation led to the posttranscriptional inhibition of NFE2L2/NRF2, which is crucial for the regulation of antioxidant molecules in cells, at two m A residues in the 3'-UTR. Knocking down ALKBH5 subsequently increased the expression of NFE2L2/NRF2 and increased the resistance of HPSCC cells to ferroptosis. In addition, m A-mediated NFE2L2/NRF2 stabilization was dependent on the m A reader IGF2BP2. We suggest that ALKBH5 dysregulates NFE2L2/NRF2 expression in HPSCC through an m A-IGF2BP2-dependent mechanism.

CONCLUSION

Together, these results have revealed an association between the ALKBH5-NFE2L2/NRF2 axis and ferroptosis, providing insight into the functional importance of reversible mRNA m A methylation and its modulators in HPSCC.

摘要

背景

作为真核生物中转录后最丰富的内部 mRNA 修饰，N6-甲基腺苷（m A）近年来引起了极大的科学兴趣。然而，m A 甲基化机制在下咽鳞状细胞癌（HPSCC）中对铁死亡调控的功能重要性仍不清楚。

方法

我们进行了生物信息学分析、细胞生物学分析、转录组范围的 m A 测序（m A-seq、MeRIP-seq）、RNA 测序（RNA-seq）和 RNA 免疫沉淀测序（RIP-seq），随后进行了 m A 点印迹、MeRIP-qPCR、RIP-qPCR 和双荧光素酶报告基因检测。

结果

结果表明，ALKBH5 介导的 m A 去甲基化导致 NFE2L2/NRF2 的转录后抑制，这对于细胞中抗氧化分子的调节至关重要，在 3'-UTR 的两个 m A 残基上。敲低 ALKBH5 随后增加了 NFE2L2/NRF2 的表达，并增加了 HPSCC 细胞对铁死亡的抗性。此外，m A 介导的 NFE2L2/NRF2 稳定依赖于 m A 阅读器 IGF2BP2。我们提出，ALKBH5 通过 m A-IGF2BP2 依赖的机制在上皮细胞癌中调节 NFE2L2/NRF2 的表达。

结论

综上所述，这些结果揭示了 ALKBH5-NFE2L2/NRF2 轴与铁死亡之间的关联，为可逆 mRNA m A 甲基化及其在 HPSCC 中的调节剂的功能重要性提供了新的见解。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/817f/9279968/d58dff25829c/JCLA-36-e24514-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/817f/9279968/2f1f30580925/JCLA-36-e24514-g001.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/817f/9279968/a9086f6ec06c/JCLA-36-e24514-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/817f/9279968/f445a7d220a9/JCLA-36-e24514-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/817f/9279968/fccf8a2cb322/JCLA-36-e24514-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/817f/9279968/c7e3281a02ad/JCLA-36-e24514-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/817f/9279968/d58dff25829c/JCLA-36-e24514-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/817f/9279968/2f1f30580925/JCLA-36-e24514-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/817f/9279968/16343417f9db/JCLA-36-e24514-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/817f/9279968/a9086f6ec06c/JCLA-36-e24514-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/817f/9279968/f445a7d220a9/JCLA-36-e24514-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/817f/9279968/fccf8a2cb322/JCLA-36-e24514-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/817f/9279968/c7e3281a02ad/JCLA-36-e24514-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/817f/9279968/d58dff25829c/JCLA-36-e24514-g007.jpg

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