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首页> 外文期刊>The FASEB Journal >Prolyl isomerase Pin1 negatively regulates the stability of SUV39H1 to promote tumorigenesis in breast cancer.
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Prolyl isomerase Pin1 negatively regulates the stability of SUV39H1 to promote tumorigenesis in breast cancer.

机译：脯氨酰异构酶 Pin1 负调控SUV39H1的稳定性，以促进乳腺癌的肿瘤发生。

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摘要

Pin1, a conserved eukaryotic peptidyl-prolyl cis/trans isomerase, has profound effects on numerous key-signaling molecules, and its deregulation contributes to disease, particularly cancer. Although Pin1-mediated prolyl isomerization of protein servers as a regulatory switch in signaling pathways, the significance of proline isomerase activity in chromatin modifying complex remains unclear. Here, we identify Pin1 as a key negative regulator for suppressor of variegation 3-9 homologue 1 (SUV39H1) stability, a major methyltransferase responsible for histone H3 trimethylation on Lys9 (H3K9me3). Pin1 interacts with SUV39H1 in a phosphorylation-dependent manner and promotes ubiquitination-mediated degradation of SUV39H1. Consequently, Pin1 reduces SUV39H1 abundance and suppresses SUV39H1 ability to induce H3K9me3. In contrast, depletion of Pin1 in cancer cells leads to elevated SUV39H1 expression, which subsequently increases H3K9me3, inhibiting tumorigenecity of cancer cells. In a xenograft model with 4T1 metastatic mouse breast carcinoma cells, Pin1 overexpression increases tumor growth, whereas SUV39H1 overexpression abrogates it. In human breast cancer patients, immunohistochemical staining shows that Pin1 levels are negatively correlated with SUV39H1 as well as H3K9me3 levels. Thus, Pin1-mediated reduction of SUV39H1 stability contributes to convey oncogenic signals for aggressiveness of human breast cancer, suggesting that Pin1 may be a promising drug target for anticancer therapy.-Khanal, P., Kim, G., Lim, S.-C., Yun, H.-J., Lee, K. Y., Choi, H.-K., Choi, H. S. Prolyl isomerase Pin1 negatively regulates the stability of SUV39H1 to promote tumorigenesis in breast cancer.
机译：Pin1 是一种保守的真核肽基-脯氨酰顺式/反式异构酶，对许多关键信号分子具有深远的影响，其失调会导致疾病，尤其是癌症。尽管 Pin1 介导的蛋白质服务器的脯氨酰异构化作为信号通路的调节开关，但脯氨酸异构酶活性在染色质修饰复合物中的意义仍不清楚。在这里，我们将 Pin1 确定为杂色 3-9 同源物 1 （SUV39H1） 稳定性抑制因子的关键负调节因子，这是一种负责 Lys9 （H3K9me3） 上组蛋白 H3 三甲基化的主要甲基转移酶。Pin1 以磷酸化依赖性方式与 SUV39H1 相互作用，并促进泛素化介导的SUV39H1降解。因此，Pin1 降低SUV39H1丰度并抑制SUV39H1诱导 H3K9me3 的能力。相反，癌细胞中 Pin1 的耗竭导致 SUV39H1 表达升高，随后增加 H3K9me3，抑制癌细胞的肿瘤发生性。在具有 4T1 转移性小鼠乳腺癌细胞的异种移植模型中，Pin1 过表达会增加肿瘤生长，而 SUV39H1 过表达会消除肿瘤生长。在人类乳腺癌患者中，免疫组织化学染色显示 Pin1 水平与 SUV39H1 以及 H3K9me3 水平呈负相关。因此，Pin1介导的SUV39H1稳定性降低有助于传达人类乳腺癌侵袭性的致癌信号，表明Pin1可能是抗癌治疗的有前途的药物靶点SUV39H1。

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