MYC-activated RNA N6-methyladenosine reader IGF2BP3 promotes cell proliferation and metastasis in nasopharyngeal carcinoma.
MYC-activated RNA N6-methyladenosine reader IGF2BP3 promotes cell proliferation and metastasis in nasopharyngeal carcinoma.
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DOI：
10.1038/s41420-022-00844-6
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发表时间：
2022-02-08
影响因子：
7
通讯作者：
He X
中科院分区：
文献类型：
--
作者：
Du M;Peng Y;Li Y;Sun W;Zhu H;Wu J;Zong D;Wu L;He X
N6-甲基腺苷 (m6A) 修饰是真核细胞中最丰富的 RNA 修饰。 IGF2BP3 是一种著名的 m6A 读取器，在许多癌症中失调，但其在鼻咽癌 (NPC) 中的作用仍不清楚。在这项工作中，IGF2BP3 在鼻咽癌组织和细胞中上调。高水平的IGF2BP3与晚期临床分期、淋巴结转移和不良预后呈正相关。此外，IGF2BP3在体外和体内加速了鼻咽癌细胞肿瘤的进展和转移。上游机制分析表明头颈部肿瘤中IGF2BP3的高表达主要是由于mRNA水平的扩增。荧光素酶实验和染色质免疫沉淀实验（CHIP）显示MYC有效结合到IGF2BP3的启动子上，从而提高其转录活性。结果还表明IGF2BP3不仅与KPNA2表达呈正相关，而且还调节KPNA2的表达。 m6A RNA免疫沉淀（MeRIP）和RNA稳定性实验验证，沉默IGF2BP3显着抑制KPNA2的m6A修饰水平，从而稳定KPNA2的mRNA稳定性。拯救实验证明，抑制或过表达IGF2BP3对NPC细胞的作用可被KPNA2部分逆转。总的来说，MYC 激活的 IGF2BP3 通过影响 m6A 修饰的 KPNA2 的稳定性来促进 NPC 细胞增殖和转移。我们的研究结果提供了新的见解，即 IGF2BP3 可能作为鼻咽癌治疗的新分子标记和潜在治疗靶点。
N6-Methyladenosine (m6A) modification is the most abundant RNA modification in eukaryotic cells. IGF2BP3, a well-known m6A reader, is deregulated in many cancers, but its role in nasopharyngeal carcinoma (NPC) remains unclear. In this work, IGF2BP3 was upregulated in NPC tissues and cells. The high level of IGF2BP3 was positively related to late clinical stages, node metastasis, and poor outcomes. Moreover, IGF2BP3 accelerated NPC cell tumor progression and metastasis in vitro and vivo. Upstream mechanism analyses indicated that the high expression of IGF2BP3 in head and neck tumors was mainly due to mRNA level amplification. Luciferase assay and chromatin immunoprecipitation assay (CHIP) depicted that MYC was effectively bound to the promoter of IGF2BP3, thereby improving its transcriptional activity. Results also showed that IGF2BP3 was not only positively correlated with KPNA2 expression but also modulated the expression of KPNA2. m6A RNA immunoprecipitation (MeRIP) and RNA stability experiments verified that silencing IGF2BP3 significantly inhibited the m6A modification level of KPNA2, thereby stabilizing the mRNA stability of KPNA2. Rescue experiments proved that the effect of inhibiting or overexpressing IGF2BP3 on NPC cells was partly reversed by KPNA2. Collectively, MYC-activated IGF2BP3 promoted NPC cell proliferation and metastasis by influencing the stability of m6A-modified KPNA2. Our findings offer new insights that IGF2BP3 may serve as a new molecular marker and potential therapeutic target for NPC treatment.
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