Stabilization of IGF2BP1 by USP10 promotes breast cancer metastasis via CPT1A in an m6A-dependent manner.
Stabilization of IGF2BP1 by USP10 promotes breast cancer metastasis via CPT1A in an m6A-dependent manner.
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USP10 对 IGF2BP1 的稳定可通过 CPT1A 以 m6A 依赖性方式促进乳腺癌转移
DOI：
10.7150/ijbs.76798
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发表时间：
2023
影响因子：
9.2
通讯作者：
Zhang W
中科院分区：
文献类型：
--
作者：
Shi J;Zhang Q;Yin X;Ye J;Gao S;Chen C;Yang Y;Wu B;Fu Y;Zhang H;Wang Z;Wang B;Zhu Y;Wu H;Yao Y;Xu G;Wang Q;Wang S;Zhang W
转移导致绝大多数乳腺癌死亡。越来越多的证据表明，N6-甲基腺苷（m6 A）修饰及其相关调节因子在乳腺癌转移中起着关键作用。在这里，我们发现m6 A阅读器IGF 2BP 1的过表达与乳腺癌患者的转移临床相关。此外，IGF 2BP 1在体外和体内促进远处转移。从机制上讲，我们首先将USP 10鉴定为IGF 2BP 1去泛素化酶。USP 10可以结合、去泛素化和稳定IGF 2BP 1，导致其在乳腺癌中的较高表达水平。此外，通过MeRIP-seq和实验验证，我们发现IGF 2BP 1直接识别并结合CPT 1A mRNA上的m6 A位点，并增强其稳定性，最终介导IGF 2BP 1诱导的乳腺癌转移。在临床样本中，USP 10水平与IGF 2BP 1和CPT 1A水平相关，具有高水平USP 10，IGF 2BP 1和CPT 1A的乳腺癌患者的预后最差。因此，这些发现表明USP 10/IGF 2BP 1/CPT 1A轴促进乳腺癌转移，并且该轴可能是乳腺癌的有希望的预后生物标志物和治疗靶点。
Metastasis leads to the vast majority of breast cancer mortality. Increasing evidence has shown that N6-methyladenosine (m6A) modification and its associated regulators play a pivotal role in breast cancer metastasis. Here, we showed that overexpression of the m6A reader IGF2BP1 was clinically correlated with metastasis in breast cancer patients. Moreover, IGF2BP1 promoted distant metastasis in vitro and in vivo. Mechanistically, we first identified USP10 as the IGF2BP1 deubiquitinase. USP10 can bind to, deubiquitinate, and stabilize IGF2BP1, resulting in its higher expression level in breast cancer. Furthermore, by MeRIP-seq and experimental verification, we found that IGF2BP1 directly recognized and bound to the m6A sites on CPT1A mRNA and enhanced its stability, which ultimately mediated IGF2BP1-induced breast cancer metastasis. In clinical samples, USP10 levels correlated with IGF2BP1 and CPT1A levels, and breast cancer patients with high levels of USP10, IGF2BP1, and CPT1A had the worst outcome. Therefore, these findings suggest that the USP10/IGF2BP1/CPT1A axis facilitates breast cancer metastasis, and this axis may be a promising prognostic biomarker and therapeutic target for breast cancer.
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影响因子：
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作者：
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