Fangchinoline suppresses conjunctival melanoma by directly binding FUBP2 and inhibiting the homologous recombination pathway
Bao Keting, Li Yongyun, Wei Jinlian, Li Ruoxi, Yang Jie, Shi Jiahao, Li Baoli, Zhu Jin, Mao Fei, Jia Renbing, Li Jian
Journal：Cell Death & Disease
IF：8.47
DOI：10.1038/s41419-021-03653-4
PMID：33828201
Published：2021-04-07
research field：分子生物学干细胞生物学细胞分化再生医学
Abstract
Conjunctival melanoma (CM) is a rare and fatal ocular tumour with poor prognosis. There is an urgent need of effective therapeutic drugs against CM. Here, we reported the discovery of a novel potential therapeutic target for CM. Through phenotypic screening of our in-house library, fangchinoline was discovered to significantly inhibit the growth of CM cells including CM-AS16, CRMM1, CRMM2 and CM2005.1. Further mechanistic experiments indicated that fangchinoline suppressed the homologous recombination (HR)-directed DNA repair by binding with far upstream element binding protein 2 (FUBP2) and downregulating the expression of HR factors BRCA1 and RAD51. In vitro and in vivo antitumour experiments revealed that fangchinoline increased the efficacy of cisplatin by blocking HR factors and reduced the drug dose and toxicity. In conclusion, our work provides a promising therapeutic strategy for the treatment of CM that is worthy of extensive preclinical investigation.
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