Institute of Biomedicine (IBIOMED), Campus Universitario, 24071, Leon, Spain.
Curr Med Chem. 2014 Apr;21(10):1231-46. doi: 10.2174/0929867321666131228205703.
Human forkhead box class O (FoxO) transcription factors, activated in response to a wide range of external stimuli, like growth factors, insulin, nutrient levels and oxidative stress, are able to control several specific geneexpression programs. Besides their clear implication in metabolic processes, they appear to play a relevant role in tumour suppression by upregulation of genes involved in cell cycle arrest or apoptosis. Recent research efforts provide new insights into the molecular modulation of FoxO in liver cancer and disclose potential opportunities for developing new antitumor drugs. Through an intricate regulatory model, achieved via several post-translational modifications, including phosphorylation, acetylation, and ubiquitination, which control their subcellular localization and DNA binding activity, FoxO factors act as tumour suppressors. Low levels of FoxOs are associated with poor prognosis in cancer patients, and seem to confer chemotherapy resistance. Within FoxO members, FoxO3a appears to present anti-tumour properties in hepatocellular carcinoma, inducing the expression of pro-apoptotic genes, or interfering with signaling cascades commonly altered in this disease such as Wnt/β-catenin, PI3K/AKT/mTOR or MAPKs pathways. Here, we describe the main mechanisms of FoxO proteins regulation, and their cross-link with altered pathways in liver cancer. Moreover, based on the current knowledge of FoxO modulation, emphasis is placed on the development of novel agents which specifically activate FoxO family members and could be useful in the treatment of hepatocarcinoma.
人类叉头框转录因子 O 类（FoxO）在响应广泛的外部刺激（如生长因子、胰岛素、营养水平和氧化应激）时被激活，能够控制几种特定的基因表达程序。除了它们在代谢过程中的明显作用外，它们似乎通过上调参与细胞周期停滞或凋亡的基因在肿瘤抑制中发挥重要作用。最近的研究努力为肝癌中 FoxO 的分子调节提供了新的见解，并揭示了开发新抗肿瘤药物的潜在机会。通过几种翻译后修饰（包括磷酸化、乙酰化和泛素化）实现的复杂调节模型，控制 FoxO 的亚细胞定位和 DNA 结合活性，使其作为肿瘤抑制因子发挥作用。FoxO 水平低与癌症患者的预后不良相关，并且似乎赋予了化疗耐药性。在 FoxO 成员中，FoxO3a 在肝细胞癌中似乎具有抗肿瘤特性，诱导促凋亡基因的表达，或干扰该疾病中常见改变的信号级联，如 Wnt/β-catenin、PI3K/AKT/mTOR 或 MAPKs 途径。在这里，我们描述了 FoxO 蛋白调节的主要机制，并探讨了其与肝癌中改变的途径的交叉联系。此外，基于 FoxO 调节的现有知识，重点介绍了专门激活 FoxO 家族成员的新型药物的开发，这些药物可能对治疗肝癌有用。
