Zhuang Xuefen, Yin Shusha, Cheng Ji, Sun Wenshuang, Fang Zesen, Xiang Yujie, Peng E-Ying, Yao Yu, Li Yuting, He Xiaoyue, Lu Li, Deng Yuanfei, Huang Hongbiao, Cai Gengxi, Liao Yuning
Guangzhou Institute of Cancer Research, the Affiliated Cancer Hospital, Guangzhou Medical University, Guangzhou 510095, China; Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou 511436, China.
KingMed School of Laboratory Medicine, Guangzhou Medical University, Guangzhou 511436, China.
Pharmacol Res. 2024 Dec;210:107509. doi: 10.1016/j.phrs.2024.107509. Epub 2024 Nov 17.
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 (mA) 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 mA modification. YTHDC1 and YTHDF1 function as readers for mA-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.
在乳腺癌（BCa）进展过程中，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不清楚。N6-甲基腺苷（mA）对调节真核细胞中的RNA状态至关重要。在此，我们发现METTL14正向调节USP22和ERα的mRNA表达。机制上，METTL14与USP22和ERα mRNA有效结合，从而通过mA修饰增强它们的稳定性。YTHDC1和YTHDF1分别作为mA修饰的USP22和ERα的读取蛋白。此外，METTL14通过USP22-ERα-细胞周期蛋白D1轴促进ERα BCa的生长和迁移。强制表达USP22/ERα可显著逆转METTL14缺失诱导的BCa生长和迁移抑制。此外，我们对临床样本的分析表明，METTL14、USP22和ERα在BCa组织中的表达上调且相关。总体而言，我们的数据揭示了METTL14-USP22-ERα轴在BCa进展中的关键作用，这进一步为治疗BCa提供了一个可成药靶点。
