Obstetrics and Gynecology Center, Department of Gynecology, Zhujiang Hospital, Southern Medical University, No. 253, Industry Avenue, Haizhu District, Guangzhou, 510280, Guangdong, China.
Department of Gynecology, Jiangxi Maternal and Child Health Hospital, Nanchang, 336000, China.
Mol Med. 2024 Sep 12;30(1):147. doi: 10.1186/s10020-024-00915-7.
The complex interplay between Sirtuin 1 (SIRT1) and FOXO3 in endometrial cancer (EC) remains understudied. This research aims to unravel the interactions of deacetylase SIRT1 and transcription factor FOXO3 in EC, focusing on their impact on mitophagy and hormone resistance.
High-throughput sequencing, cell experiments, and bioinformatics tools were employed to investigate the roles and interactions of SIRT1 and FOXO3 in EC. Co-immunoprecipitation (Co-IP) assay was used to assess the interaction between SIRT1 and FOXO3 in RL95-2 cells. Functional assays were used to assess cell viability, proliferation, migration, invasion, apoptosis, and the expression of related genes and proteins. A mouse model of EC was established to evaluate tumor growth and hormone resistance under different interventions. Immunohistochemistry and TUNEL assays were used to assess protein expression and apoptosis in tumor tissues.
High-throughput transcriptome sequencing revealed a close association between SIRT1, FOXO3, and EC development. Co-IP showed a protein-protein interaction between SIRT1 and FOXO3. Overexpression of SIRT1 enhanced FOXO3 deacetylation and activity, promoting BNIP3 transcription and PINK1/Parkin-mediated mitophagy, which in turn promoted cell proliferation, migration, invasion, and inhibited apoptosis in vitro, as well as increased tumor growth and hormone resistance in vivo. These findings highlighted SIRT1 as an upstream regulator and potential therapeutic target in EC.
This study reveals a novel molecular mechanism underlying the functional relevance of SIRT1 in regulating mitophagy and hormone resistance through the deacetylation of FOXO3 in EC, thereby providing valuable insights for new therapeutic strategies.
Sirtuin 1（SIRT1）和 FOXO3 之间的复杂相互作用在子宫内膜癌（EC）中仍未得到充分研究。本研究旨在揭示 EC 中去乙酰化酶 SIRT1 和转录因子 FOXO3 的相互作用，重点研究它们对线粒体自噬和激素抵抗的影响。
采用高通量测序、细胞实验和生物信息学工具研究 SIRT1 和 FOXO3 在 EC 中的作用和相互作用。采用免疫共沉淀（Co-IP）检测 RL95-2 细胞中 SIRT1 和 FOXO3 的相互作用。采用功能测定评估细胞活力、增殖、迁移、侵袭、凋亡以及相关基因和蛋白的表达。建立 EC 小鼠模型，评估不同干预措施下肿瘤生长和激素抵抗情况。采用免疫组化和 TUNEL 检测评估肿瘤组织中蛋白表达和细胞凋亡。
高通量转录组测序揭示了 SIRT1、FOXO3 与 EC 发展之间的密切关联。Co-IP 显示 SIRT1 和 FOXO3 之间存在蛋白-蛋白相互作用。SIRT1 的过表达增强了 FOXO3 的去乙酰化和活性，促进了 BNIP3 的转录和 PINK1/Parkin 介导的线粒体自噬，进而促进了细胞增殖、迁移、侵袭，并抑制了体外凋亡，以及体内肿瘤生长和激素抵抗。这些发现强调了 SIRT1 作为 EC 中一种潜在的治疗靶点和上游调节剂的作用。
本研究揭示了 SIRT1 通过去乙酰化 FOXO3 调节 EC 中线粒体自噬和激素抵抗的功能相关性的新分子机制，为新的治疗策略提供了有价值的见解。
