Center for Human Genome Research, Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, PR China.
Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Cancer Lett. 2021 Jan 28;497:28-40. doi: 10.1016/j.canlet.2020.10.014. Epub 2020 Oct 15.
Angiogenesis factors are widely known to promote tumor growth by increasing tumor angiogenesis in the tumor microenvironment, however, little is known whether their intracellular function is involved in tumorigenesis. Here we show that AGGF1 acts as a tumor suppressor by regulating p53 when acting inside tumor cells. AGGF1 antagonizes MDM2 function to inhibit p53 ubiquitination, increases the acetylation, phosphorylation, stability and expression levels of p53, activates transcription of p53 target genes, and regulates cell proliferation, cell cycle, and apoptosis. AGGF1 also interacts with p53 through the FHA domain. Somatic AGGF1 variants in the FHA domain in human tumors, including p.Q467H, p.Y469 N, and p.N483T, inhibit AGGF1 activity on tumor suppression. These results identify a key role for AGGF1 in an AGGF1-MDM2-p53 signaling axis with important functions in tumor suppression, and uncover a novel trans-tumor-suppression mechanism dependent on p53. This study has potential implications in diagnosis and therapies of cancer.
血管生成因子通过增加肿瘤微环境中的肿瘤血管生成而广泛被认为促进肿瘤生长，然而，它们的细胞内功能是否参与肿瘤发生则知之甚少。在这里，我们表明 AGGF1 通过在肿瘤细胞内作用于 p53 来发挥肿瘤抑制因子的作用。AGGF1 拮抗 MDM2 的功能以抑制 p53 的泛素化，增加 p53 的乙酰化、磷酸化、稳定性和表达水平，激活 p53 靶基因的转录，并调节细胞增殖、细胞周期和细胞凋亡。AGGF1 还通过 FHA 结构域与 p53 相互作用。人类肿瘤中 FHA 结构域中的体细胞 AGGF1 变异，包括 p.Q467H、p.Y469N 和 p.N483T，抑制 AGGF1 对肿瘤抑制的活性。这些结果确定了 AGGF1 在 AGGF1-MDM2-p53 信号轴中的关键作用，该信号轴在肿瘤抑制中具有重要功能，并揭示了一种依赖于 p53 的新的跨肿瘤抑制机制。这项研究对癌症的诊断和治疗具有潜在意义。
