METTL14-mediated m⁶A modification enhances USP22-ERα axis to drive breast cancer malignancy.

IF 9.1 2区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacological research Pub Date : 2024-11-16 DOI:10.1016/j.phrs.2024.107509

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

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引用次数: 0

Abstract

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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METTL14 介导的 m6A 修饰增强 USP22-ERα 轴，从而驱动乳腺癌恶性发展。

在乳腺癌（BCa）的发展过程中，雌激素受体α（ERα）的丰度和活性受到泛素特异性肽酶 22（USP22）的严格调控。然而，USP22-ERα轴上的转录后修饰仍然难以捉摸。N6-甲基腺苷（m6A）对于调节真核细胞中的 RNA 状态至关重要。在这里，我们发现 METTL14 能正向调节 USP22 和 ERα 的 mRNA 表达。从机理上讲，METTL14 能与 USP22 和 ERα mRNA 有效结合，从而通过 m6A 修饰增强它们的稳定性。YTHDC1 和 YTHDF1 分别作为经 m6A 修饰的 USP22 和 ERα 的阅读器。此外，METTL14 通过 USP22-ERα-Cyclin D1 轴促进 ERα+ BCa 的生长和迁移。USP22/ERα的强制表达能显著逆转METTL14耗竭引起的BCa生长和迁移抑制。此外，我们对临床样本的分析表明，在 BCa 组织中，METTL14、USP22 和 ERα 的表达是上调和相关的。总之，我们的研究结果揭示了METTL14-USP22-ERα轴在BCa进展过程中的关键作用，这进一步为治疗BCa提供了一个药物靶点。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Pharmacological research 医学-药学

CiteScore

18.70

自引率

3.20%

发文量

491

审稿时长

8 days

期刊介绍： 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.