Department of Obstetrics and Gynecology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, PR China; Department of Gynecologic Oncology, Hunan Cancer Hospital, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, PR China.
Department of Obstetrics and Gynecology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, PR China; Department of Obstetrics and Gynecology, Shanghai Eighth People's Hospital Affiliated to Jiangsu University, Shanghai, 200233, PR China.
Cancer Lett. 2021 Aug 10;513:36-49. doi: 10.1016/j.canlet.2021.04.024. Epub 2021 May 13.
Endometrial cancer (EC) is becoming one of the most common gynecologic malignancies. Lipid metabolism is a hallmark feature of cancers. The molecular mechanisms underlying lipid metabolism in EC remain unclear. In this study, we revealed that many lipid metabolism-related genes were aberrantly expressed in endometrial cancer tissues, especially ACLY. Upregulated ACLY promoted EC cell proliferation and colony formation, and attenuated apoptosis. Mechanistically, cotreatment with obesity-related factors (estradiol, insulin and leptin) promoted nuclear translocation of ACLY through Akt-mediated phosphorylation of ACLY at Ser455. Nuclear-localized ACLY increased histone acetylation levels, thus resulting in upregulation of pyrimidine metabolism genes, such as DHODH. Moreover, STAT3 altered the ACLY expression at the transcriptional level via directly binding to its promoter region. In conclusion, our findings clarify the roles and mechanisms of ACLY in endometrial cancer and ACLY could link obesity risk factors to the regulation of histone acetylation. We believe that novel therapeutic strategies for EC can be designed by targeting the ACLY axis.
子宫内膜癌（EC）正成为最常见的妇科恶性肿瘤之一。脂质代谢是癌症的一个显著特征。EC 中脂质代谢的分子机制尚不清楚。在这项研究中，我们揭示了许多脂质代谢相关基因在子宫内膜癌组织中异常表达，特别是 ACLY。上调的 ACLY 促进 EC 细胞增殖和集落形成，并减弱细胞凋亡。在机制上，肥胖相关因素（雌二醇、胰岛素和瘦素）通过 Akt 介导的 ACLY 在 Ser455 上的磷酸化促进 ACLY 的核易位。核定位的 ACLY 增加组蛋白乙酰化水平，从而导致嘧啶代谢基因（如 DHODH）的上调。此外，STAT3 通过直接结合其启动子区域在转录水平改变 ACLY 的表达。总之，我们的研究结果阐明了 ACLY 在子宫内膜癌中的作用和机制，并且 ACLY 可以将肥胖风险因素与组蛋白乙酰化的调节联系起来。我们相信，通过靶向 ACLY 轴可以为 EC 设计新的治疗策略。
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