Wang Gui-Zhen, Liu Yong-Qiang, Cheng Xin, Zhou Guang-Biao
Division of Molecular Carcinogenesis and Targeted Therapy for Cancer, State Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.
University of Chinese Academy of Sciences, Beijing, China.
Cancer Sci. 2015 Jul;106(7):902-8. doi: 10.1111/cas.12679. Epub 2015 May 26.
The Fanconi anemia (FA) pathway plays a key role in interstrand crosslink (ICL) repair and maintenance of the genomic stability, while inhibition of this pathway may sensitize cancer cells to DNA ICL agents and ionizing radiation (IR). The active FA core complex acts as an E3 ligase to monoubiquitinate FANCD2, which is a functional readout of an activated FA pathway. In the present study, we aimed to identify FANCD2-targeting agents, and found that the natural compound celastrol induced degradation of FANCD2 through the ubiquitin-proteasome pathway. We demonstrated that celastrol downregulated the basal and DNA damaging agent-induced monoubiquitination of FANCD2, followed by proteolytic degradation of the substrate. Furthermore, celastrol treatment abrogated the G2 checkpoint induced by IR, and enhanced the ICL agent-induced DNA damage and inhibitory effects on lung cancer cells through depletion of FANCD2. These results indicate that celastrol is a FANCD2 inhibitor that could interfere with the monoubiquitination and protein stability of FANCD2, providing a novel opportunity to develop FA pathway inhibitor and combinational therapy for malignant neoplasms.
范可尼贫血（FA）通路在链间交联（ICL）修复和基因组稳定性维持中起关键作用，而抑制该通路可能使癌细胞对DNA ICL剂和电离辐射（IR）敏感。活性FA核心复合物作为一种E3连接酶，使FANCD2单泛素化，这是激活的FA通路的一个功能读数。在本研究中，我们旨在鉴定靶向FANCD2的药物，并发现天然化合物雷公藤红素通过泛素-蛋白酶体途径诱导FANCD2降解。我们证明雷公藤红素下调FANCD2的基础水平和DNA损伤剂诱导的单泛素化，随后底物发生蛋白水解降解。此外，雷公藤红素处理消除了IR诱导的G2期检查点，并通过消耗FANCD2增强了ICL剂诱导的DNA损伤和对肺癌细胞的抑制作用。这些结果表明，雷公藤红素是一种FANCD2抑制剂，可干扰FANCD2的单泛素化和蛋白质稳定性，为开发FA通路抑制剂和恶性肿瘤联合治疗提供了新的机会。
