<br>IGF2BP2 通过招募 EIF4A1 促进 m6A 修饰的 CDK6 翻译启动过程来驱动三阴性乳腺癌的细胞周期进展,Advanced Science

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IGF2BP2 通过招募 EIF4A1 促进 m6A 修饰的 CDK6 翻译启动过程来驱动三阴性乳腺癌的细胞周期进展
Advanced Science ( IF 14.3 ) Pub Date : 2023-11-20 , DOI: 10.1002/advs.202305142
Tian Xia ₁ , Xin-Yuan Dai ₁ , Ming-Yi Sang ₁ , Xu Zhang ₁ , Feng Xu ₁ , Jing Wu ₁ , Liang Shi ₁ , Ji-Fu Wei ₂ , Qiang Ding ₁

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IGF2BP2 是一种新发现的 N6-甲基腺苷 (m6A) 读取器，与许多肿瘤的不良预后相关。然而，其在乳腺癌，特别是三阴性乳腺癌（TNBC）中的作用和相关机制仍不清楚。本研究发现IGF2BP2由于其启动子区甲基化水平较低，在TNBC中高表达。功能和力学研究表明，IGF2BP2可以通过m6A依赖性方式直接调节CDK6，促进TNBC增殖和细胞周期的G1/S期转变。令人惊讶的是，IGF2BP2 对 CDK6 蛋白水平的调节与翻译起始期间翻译速率的变化有关，而不是与 mRNA 稳定性有关。此外，发现EIF4A1被IGF2BP2招募来促进CDK6的翻译输出，这为IGF2BP2在m6A甲基化和翻译之间的调节作用提供了新的证据。 TNBC 细胞中 IGF2BP2 的下调可以增强对 CDK4/6 抑制剂 abemaciclib 的敏感性。综上所述，我们的研究揭示IGF2BP2可以通过招募EIF4A1促进CDK6的翻译输出，也为TNBC的诊断和治疗提供潜在的治疗靶点，并为拓宽CDK4/6抑制剂的药物适应症提供新策略。

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IGF2BP2 Drives Cell Cycle Progression in Triple-Negative Breast Cancer by Recruiting EIF4A1 to Promote the m6A-Modified CDK6 Translation Initiation Process

IGF2BP2 is a new identified N6-methyladenosine (m6A) reader and associated with poor prognosis in many tumors. However, its role and related mechanism in breast cancer, especially in triple-negative breast cancer (TNBC), remains unclear. In this study, it is found that IGF2BP2 is highly expressed in TNBC due to the lower methylation level in its promoter region. Functional and mechanical studies displayed that IGF2BP2 could promote TNBC proliferation and the G1/S phase transition of the cell cycle via directly regulating CDK6 in an m6A-dependent manner. Surprising, the regulation of protein levels of CDK6 by IGF2BP2 is related to the changes in translation rate during translation initiation, rather than mRNA stability. Moreover, EIF4A1 is found to be recruited by IGF2BP2 to promote the translation output of CDK6, providing new evidence for a regulatory role of IGF2BP2 between m6A methylation and translation. Downregulation of IGF2BP2 in TNBC cell could enhance the sensitivity to abemaciclib, a CDK4/6 inhibitor. To sum up, our study revealed IGF2BP2 could facilitate the translation output of CDK6 via recruiting EIF4A1 and also provided a potential therapeutic target for the diagnosis and treatment of TNBC, as well as a new strategy for broadening the drug indications for CDK4/6 inhibitors.

更新日期：2023-11-20

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