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N6-甲基腺嘌呤去甲基酶 ALKBH5 通过降低 PHF20 mRNA 甲基化来抑制结直肠癌细胞的进展。

N6-methyladenosine demethylase ALKBH5 suppresses colorectal cancer progression potentially by decreasing PHF20 mRNA methylation.

机构信息

Department of Gastroenterological Surgery, Peking University People's Hospital, Beijing, China.

Laboratory of Surgical Oncology, Beijing Key Laboratory of Colorectal Cancer Diagnosis and Treatment Research, Peking University People's Hospital, Beijing, China.

出版信息

Clin Transl Med. 2022 Aug;12(8):e940. doi: 10.1002/ctm2.940.

DOI:10.1002/ctm2.940
PMID:35979628
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9386323/
Abstract

BACKGROUND

As the most widespread mRNAs modification, N6-methyladenosine (m A) is dynamically and reversibly modulated by methyltransferases and demethylases. ALKBH5 is a major demethylase, and plays vital roles in the progression of cancers. However, the role and mechanisms of ALKBH5 in colorectal cancer (CRC) is unclear.

RESULTS

Herein, we discovered that in CRC, downregulated ALKBH5 was closely related to poor prognosis of CRC patients. Functionally, our results demonstrated that knockdown of ALKBH5 enhanced the proliferation, migration and invasion of LOVO and RKO in vitro, while overexpression of ALKBH5 inhibited the functions of these cells. The results also demonstrated that knockdown of ALKBH5 promoted subcutaneous tumorigenesis of LOVO in vivo, while overexpression of ALKBH5 suppressed this ability. Mechanistically, results from joint analyses of MeRIP-seq and RNA-seq indicated that PHF20 mRNA was a key molecule that was regulated by ALKBH5-mediated m A modification. Further experiments indicated that ALKBH5 may inhibit stability of PHF20 mRNA by removing the m A modification of PHF20 mRNA 3'UTR.

CONCLUSIONS

ALKBH5 suppresses CRC progression by decreasing PHF20 mRNA methylation. ALKBH5-mediated m A modification of PHF20 mRNA can serve as a hopeful strategy for the intervention and treatment of CRC.

摘要

背景

作为最广泛的 mRNA 修饰，N6-甲基腺苷（m A）可被甲基转移酶和去甲基酶动态且可逆地调节。ALKBH5 是主要的去甲基酶，在癌症的进展中发挥重要作用。然而，ALKBH5 在结直肠癌（CRC）中的作用和机制尚不清楚。

结果

在此，我们发现，在 CRC 中，下调的 ALKBH5 与 CRC 患者的不良预后密切相关。功能上，我们的结果表明，敲低 ALKBH5 增强了 LOVO 和 RKO 细胞的体外增殖、迁移和侵袭能力，而过表达 ALKBH5 则抑制了这些细胞的功能。结果还表明，敲低 ALKBH5 促进了 LOVO 细胞在体内的皮下肿瘤生成，而过表达 ALKBH5 则抑制了这种能力。在机制上，MeRIP-seq 和 RNA-seq 的联合分析结果表明，PHF20 mRNA 是受 ALKBH5 介导的 m A 修饰调节的关键分子。进一步的实验表明，ALKBH5 可能通过去除 PHF20 mRNA 3'UTR 的 m A 修饰来抑制 PHF20 mRNA 的稳定性。

结论

ALKBH5 通过降低 PHF20 mRNA 甲基化来抑制 CRC 进展。ALKBH5 介导的 PHF20 mRNA 的 m A 修饰可作为 CRC 干预和治疗的有希望的策略。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e42d/9386323/30033d9de4dd/CTM2-12-e940-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e42d/9386323/c8df7e574f54/CTM2-12-e940-g010.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e42d/9386323/60539e201973/CTM2-12-e940-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e42d/9386323/bef36bdfd3db/CTM2-12-e940-g009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e42d/9386323/aee3f06c9839/CTM2-12-e940-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e42d/9386323/dbf53c1f6253/CTM2-12-e940-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e42d/9386323/74a64d822ae2/CTM2-12-e940-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e42d/9386323/fd52bae7e732/CTM2-12-e940-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e42d/9386323/e5eb0a3e9016/CTM2-12-e940-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e42d/9386323/30033d9de4dd/CTM2-12-e940-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e42d/9386323/c8df7e574f54/CTM2-12-e940-g010.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e42d/9386323/60539e201973/CTM2-12-e940-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e42d/9386323/bef36bdfd3db/CTM2-12-e940-g009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e42d/9386323/aee3f06c9839/CTM2-12-e940-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e42d/9386323/dbf53c1f6253/CTM2-12-e940-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e42d/9386323/74a64d822ae2/CTM2-12-e940-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e42d/9386323/fd52bae7e732/CTM2-12-e940-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e42d/9386323/e5eb0a3e9016/CTM2-12-e940-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e42d/9386323/30033d9de4dd/CTM2-12-e940-g007.jpg

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