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蜗牛/PRMT5/NuRD 复合物通过 TET1 抑制促进宫颈癌中的 DNA 高甲基化。

Snail/PRMT5/NuRD complex contributes to DNA hypermethylation in cervical cancer by TET1 inhibition.

机构信息

Tianjin Key Laboratory of Inflammatory Biology, The province and ministry co-sponsored collaborative innovation center for medical epigenetics, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China.

The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China.

出版信息

Cell Death Differ. 2021 Sep;28(9):2818-2836. doi: 10.1038/s41418-021-00786-z. Epub 2021 May 5.

DOI:10.1038/s41418-021-00786-z
PMID:33953349
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8408166/
Abstract

The biological function of PRMT5 remains poorly understood in cervical cancer metastasis. Here, we report that PRMT5 physically associates with the transcription factor Snail and the NuRD(MTA1) complex to form a transcriptional-repressive complex that catalyzes the symmetrical histone dimethylation and deacetylation. This study shows that the Snail/PRMT5/NuRD(MTA1) complex targets genes, such as TET1 and E-cadherin, which are critical for epithelial-mesenchymal transition (EMT). This complex also affects the conversion of 5mC to 5hmC. This study demonstrates that the Snail/PRMT5/NuRD(MTA1) complex promotes the invasion and metastasis of cervical cancer in vitro and in vivo. This study also shows that PRMT5 expression is upregulated in cervical cancer and various human cancers, and the PRMT5 inhibitor EPZ015666 suppresses EMT and the invasion potential of cervical cancer cells by disinhibiting the expression of TET1 and increasing 5hmC, suggesting that PRMT5 is a potential target for cancer therapy.

摘要

PRMT5 在宫颈癌转移中的生物学功能仍知之甚少。在这里，我们报告 PRMT5 与转录因子 Snail 和 NuRD（MTA1）复合物物理结合，形成一个转录抑制性复合物，催化对称组蛋白二甲基化和去乙酰化。这项研究表明，Snail/PRMT5/NuRD（MTA1）复合物靶向 TET1 和 E-钙黏蛋白等基因，这些基因对于上皮-间充质转化（EMT）至关重要。该复合物还影响 5mC 向 5hmC 的转化。本研究表明，Snail/PRMT5/NuRD（MTA1）复合物促进了宫颈癌在体外和体内的侵袭和转移。本研究还表明，PRMT5 在宫颈癌和各种人类癌症中表达上调，PRMT5 抑制剂 EPZ015666 通过抑制 TET1 的表达和增加 5hmC 来抑制 EMT 和宫颈癌细胞的侵袭潜能，提示 PRMT5 可能是癌症治疗的潜在靶点。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fa53/8408166/9e8831d57d6b/41418_2021_786_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fa53/8408166/2f7343d456e9/41418_2021_786_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fa53/8408166/0d8ba6ef562d/41418_2021_786_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fa53/8408166/987cd413653b/41418_2021_786_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fa53/8408166/75fcf4cce9e4/41418_2021_786_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fa53/8408166/f6558d17e936/41418_2021_786_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fa53/8408166/8119debd467e/41418_2021_786_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fa53/8408166/4183f6ce6903/41418_2021_786_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fa53/8408166/9e8831d57d6b/41418_2021_786_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fa53/8408166/2f7343d456e9/41418_2021_786_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fa53/8408166/0d8ba6ef562d/41418_2021_786_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fa53/8408166/987cd413653b/41418_2021_786_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fa53/8408166/75fcf4cce9e4/41418_2021_786_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fa53/8408166/f6558d17e936/41418_2021_786_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fa53/8408166/8119debd467e/41418_2021_786_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fa53/8408166/4183f6ce6903/41418_2021_786_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fa53/8408166/9e8831d57d6b/41418_2021_786_Fig8_HTML.jpg

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