SIRT7 facilitates endometrial cancer progression by regulating PTEN stability in an estrogen-dependent manner

IF 15.7 1区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES

Nature Communications Pub Date : 2025-03-27 DOI:10.1038/s41467-025-58317-0

Zhiyi Hu, Ming Tang, Yujia Huang, Bailian Cai, Xiaoxiang Sun, Guofang Chen, Ao Huang, Xiaoqi Li, Ab Rauf Shah, Lijun Jiang, Qian Li, Xianghong Xu, Wen Lu, Zhiyong Mao, Xiaoping Wan

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Abstract

The prognosis of metastatic endometrial carcinoma (EC), one of the most common gynecological malignancies worldwide, remains poor, and the underlying driver of metastases is poorly understood. Dysregulation in estrogen-related signaling and inactivation of tumor suppressor PTEN are two essential risk factors of EC. However, whether and how they are interconnected during EC development remains unclear. Here, we demonstrate that the deacetylase SIRT7 is upregulated in EC patients and mouse models, facilitating EC progression in vitro and in vivo. Mechanistically, in an estrogen-dependent fashion, SIRT7 mediates PTEN deacetylation at K260, promoting PTEN ubiquitination by the E3 ligase NEDD4L, accelerating PTEN degradation and, consequently, expediting EC metastasis. Additionally, SIRT7 expression strongly correlates with poor survival in EC patients with wild-type PTEN, though no significant correlation is observed in PTEN mutation patients. These results lay the foundation for the study of targeting estrogen-SIRT7-PTEN axis, to restore PTEN abundance, offering potential avenues for EC therapy.

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SIRT7以雌激素依赖的方式调节PTEN的稳定性，从而促进子宫内膜癌的进展

转移性子宫内膜癌（EC）是世界范围内最常见的妇科恶性肿瘤之一，其预后仍然很差，并且转移的潜在驱动因素尚不清楚。雌激素相关信号的失调和肿瘤抑制因子PTEN的失活是EC的两个重要危险因素。然而，在电子商务发展过程中，它们是否相互关联以及如何相互关联仍不清楚。在这里，我们证明脱乙酰酶SIRT7在EC患者和小鼠模型中上调，促进体外和体内EC的进展。从机制上讲，SIRT7以雌激素依赖的方式介导PTEN在K260位点的去乙酰化，通过E3连接酶NEDD4L促进PTEN泛素化，加速PTEN降解，从而加速EC转移。此外，SIRT7表达与携带野生型PTEN的EC患者的低生存率密切相关，但在PTEN突变患者中未观察到显著相关性。这些结果为靶向雌激素- sirt7 -PTEN轴恢复PTEN丰度的研究奠定了基础，为EC治疗提供了潜在的途径。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Nature Communications Biological Science Disciplines-

CiteScore

24.90

自引率

2.40%

发文量

6928

审稿时长

3.7 months

期刊介绍： Nature Communications, an open-access journal, publishes high-quality research spanning all areas of the natural sciences. Papers featured in the journal showcase significant advances relevant to specialists in each respective field. With a 2-year impact factor of 16.6 (2022) and a median time of 8 days from submission to the first editorial decision, Nature Communications is committed to rapid dissemination of research findings. As a multidisciplinary journal, it welcomes contributions from biological, health, physical, chemical, Earth, social, mathematical, applied, and engineering sciences, aiming to highlight important breakthroughs within each domain.