Anticancer Agent Research Center, Korea Research Institute of Bioscience and Biotechnology, Cheongju, 28116, Korea.
Department of Biomolecular Science, University of Science and Technology, Daejeon, 34113, Korea.
Exp Mol Med. 2019 Feb 12;51(2):1-14. doi: 10.1038/s12276-018-0200-4.
Hypoxia-inducible factor-1α (HIF-1α) mediates tumor cell adaptation to hypoxic conditions and is a potentially important anticancer therapeutic target. We previously developed a method for synthesizing a benzofuran-based natural product, (R)-(-)-moracin-O, and obtained a novel potent analog, MO-460 that suppresses the accumulation of HIF-1α in Hep3B cells. However, the molecular target and underlying mechanism of action of MO-460 remained unclear. In the current study, we identified heterogeneous nuclear ribonucleoprotein A2B1 (hnRNPA2B1) as a molecular target of MO-460. MO-460 inhibits the initiation of HIF-1α translation by binding to the C-terminal glycine-rich domain of hnRNPA2B1 and inhibiting its subsequent binding to the 3'-untranslated region of HIF-1α mRNA. Moreover, MO-460 suppresses HIF-1α protein synthesis under hypoxic conditions and induces the accumulation of stress granules. The data provided here suggest that hnRNPA2B1 serves as a crucial molecular target in hypoxia-induced tumor survival and thus offer an avenue for the development of novel anticancer therapies.
缺氧诱导因子-1α（HIF-1α）介导肿瘤细胞适应缺氧环境，是一种潜在的重要抗癌治疗靶点。我们之前开发了一种合成苯并呋喃类天然产物（R）-（-）-moracin-O 的方法，并获得了一种新型有效的类似物 MO-460，它能抑制 Hep3B 细胞中 HIF-1α的积累。然而，MO-460 的分子靶点和作用机制尚不清楚。在本研究中，我们鉴定了异质核核糖核蛋白 A2B1（hnRNPA2B1）为 MO-460 的分子靶点。MO-460 通过与 hnRNPA2B1 的 C 端富含甘氨酸结构域结合，抑制其随后与 HIF-1α mRNA 的 3'-非翻译区结合，从而抑制 HIF-1α 翻译的起始。此外，MO-460 抑制缺氧条件下 HIF-1α的蛋白质合成，并诱导应激颗粒的积累。这里提供的数据表明，hnRNPA2B1 是缺氧诱导的肿瘤存活的关键分子靶点，因此为开发新型抗癌疗法提供了一个途径。
