{"title":"METTL14 介导的 m6A 修饰增强 USP22-ERα 轴，从而驱动乳腺癌恶性发展。","authors":"Xuefen Zhuang, Shusha Yin, Ji Cheng, Wenshuang Sun, Zesen Fang, Yujie Xiang, E-Ying Peng, Yu Yao, Yuting Li, Xiaoyue He, Li Lu, Yuanfei Deng, Hongbiao Huang, Gengxi Cai, Yuning Liao","doi":"10.1016/j.phrs.2024.107509","DOIUrl":null,"url":null,"abstract":"<p><p>The abundance and activity of estrogen receptor alpha (ERα) are tightly regulated by ubiquitin-specific peptidase 22 (USP22) during the progression of breast cancer (BCa). However, the post-transcriptional modifications on the USP22-ERα axis remain elusive. N6-methyladenosine (m<sup>6</sup>A) is critical to modulate RNA status in eukaryotic cells. Here, we find that METTL14 positively regulates the mRNA expression of USP22 and ERα. Mechanistically, METTL14 potently binds to the USP22 and ERα mRNA, and thereby enhancing their stability through m<sup>6</sup>A modification. YTHDC1 and YTHDF1 function as readers for m<sup>6</sup>A-modified USP22 and ERα, respectively. Additionally, METTL14 promotes the growth and migration of ERα<sup>+</sup> BCa via the USP22-ERα-Cyclin D1 axis. Enforced expression of USP22/ERα significantly reverses the METTL14 depletion-induced growth and migration inhibition in BCa. Moreover, our analysis of clinical samples shows that the expression of METTL14, USP22, and ERα is upregulated and correlated in BCa tissues. Overall, our findings reveal the key role of the METTL14-USP22-ERα axis in BCa progression, which further provides a druggable target to treat BCa.</p>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":" ","pages":"107509"},"PeriodicalIF":9.1000,"publicationDate":"2024-11-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"METTL14-mediated m<sup>6</sup>A modification enhances USP22-ERα axis to drive breast cancer malignancy.\",\"authors\":\"Xuefen Zhuang, Shusha Yin, Ji Cheng, Wenshuang Sun, Zesen Fang, Yujie Xiang, E-Ying Peng, Yu Yao, Yuting Li, Xiaoyue He, Li Lu, Yuanfei Deng, Hongbiao Huang, Gengxi Cai, Yuning Liao\",\"doi\":\"10.1016/j.phrs.2024.107509\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>The abundance and activity of estrogen receptor alpha (ERα) are tightly regulated by ubiquitin-specific peptidase 22 (USP22) during the progression of breast cancer (BCa). However, the post-transcriptional modifications on the USP22-ERα axis remain elusive. N6-methyladenosine (m<sup>6</sup>A) is critical to modulate RNA status in eukaryotic cells. Here, we find that METTL14 positively regulates the mRNA expression of USP22 and ERα. Mechanistically, METTL14 potently binds to the USP22 and ERα mRNA, and thereby enhancing their stability through m<sup>6</sup>A modification. YTHDC1 and YTHDF1 function as readers for m<sup>6</sup>A-modified USP22 and ERα, respectively. Additionally, METTL14 promotes the growth and migration of ERα<sup>+</sup> BCa via the USP22-ERα-Cyclin D1 axis. Enforced expression of USP22/ERα significantly reverses the METTL14 depletion-induced growth and migration inhibition in BCa. Moreover, our analysis of clinical samples shows that the expression of METTL14, USP22, and ERα is upregulated and correlated in BCa tissues. Overall, our findings reveal the key role of the METTL14-USP22-ERα axis in BCa progression, which further provides a druggable target to treat BCa.</p>\",\"PeriodicalId\":19918,\"journal\":{\"name\":\"Pharmacological research\",\"volume\":\" \",\"pages\":\"107509\"},\"PeriodicalIF\":9.1000,\"publicationDate\":\"2024-11-16\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Pharmacological research\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1016/j.phrs.2024.107509\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"PHARMACOLOGY & PHARMACY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Pharmacological research","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1016/j.phrs.2024.107509","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"PHARMACOLOGY & PHARMACY","Score":null,"Total":0}
METTL14-mediated m6A modification enhances USP22-ERα axis to drive breast cancer malignancy.
The abundance and activity of estrogen receptor alpha (ERα) are tightly regulated by ubiquitin-specific peptidase 22 (USP22) during the progression of breast cancer (BCa). However, the post-transcriptional modifications on the USP22-ERα axis remain elusive. N6-methyladenosine (m6A) is critical to modulate RNA status in eukaryotic cells. Here, we find that METTL14 positively regulates the mRNA expression of USP22 and ERα. Mechanistically, METTL14 potently binds to the USP22 and ERα mRNA, and thereby enhancing their stability through m6A modification. YTHDC1 and YTHDF1 function as readers for m6A-modified USP22 and ERα, respectively. Additionally, METTL14 promotes the growth and migration of ERα+ BCa via the USP22-ERα-Cyclin D1 axis. Enforced expression of USP22/ERα significantly reverses the METTL14 depletion-induced growth and migration inhibition in BCa. Moreover, our analysis of clinical samples shows that the expression of METTL14, USP22, and ERα is upregulated and correlated in BCa tissues. Overall, our findings reveal the key role of the METTL14-USP22-ERα axis in BCa progression, which further provides a druggable target to treat BCa.
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Pharmacological Research publishes cutting-edge articles in biomedical sciences to cover a broad range of topics that move the pharmacological field forward. Pharmacological research publishes articles on molecular, biochemical, translational, and clinical research (including clinical trials); it is proud of its rapid publication of accepted papers that comprises a dedicated, fast acceptance and publication track for high profile articles.
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