Fangchinoline suppresses conjunctival melanoma by directly binding FUBP2 and inhibiting the homologous recombination pathway

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, fangchin...

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Main Authors:	Keting Bao, Yongyun Li, Jinlian Wei, Ruoxi Li, Jie Yang, Jiahao Shi, Baoli Li, Jin Zhu, Fei Mao, Renbing Jia, Jian Li
Format:	Article
Language:	English
Published:	Nature Publishing Group 2021-04-01
Series:	Cell Death and Disease
Online Access:	https://doi.org/10.1038/s41419-021-03653-4

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spelling	doaj-cc5d174684044e10bf856777958755282021-04-11T11:05:07ZengNature Publishing GroupCell Death and Disease2041-48892021-04-0112411110.1038/s41419-021-03653-4Fangchinoline suppresses conjunctival melanoma by directly binding FUBP2 and inhibiting the homologous recombination pathwayKeting Bao0Yongyun Li1Jinlian Wei2Ruoxi Li3Jie Yang4Jiahao Shi5Baoli Li6Jin Zhu7Fei Mao8Renbing Jia9Jian Li10State Key Laboratory of Bioreactor Engineering, Shanghai Key Laboratory of New Drug Design, East China University of Science and TechnologyDepartment of Ophthalmology, Ninth People’s Hospital, Shanghai Jiao Tong University School of MedicineState Key Laboratory of Bioreactor Engineering, Shanghai Key Laboratory of New Drug Design, East China University of Science and TechnologyState Key Laboratory of Bioreactor Engineering, Shanghai Key Laboratory of New Drug Design, East China University of Science and TechnologyDepartment of Ophthalmology, Ninth People’s Hospital, Shanghai Jiao Tong University School of MedicineDepartment of Ophthalmology, Ninth People’s Hospital, Shanghai Jiao Tong University School of MedicineState Key Laboratory of Bioreactor Engineering, Shanghai Key Laboratory of New Drug Design, East China University of Science and TechnologyState Key Laboratory of Bioreactor Engineering, Shanghai Key Laboratory of New Drug Design, East China University of Science and TechnologyState Key Laboratory of Bioreactor Engineering, Shanghai Key Laboratory of New Drug Design, East China University of Science and TechnologyDepartment of Ophthalmology, Ninth People’s Hospital, Shanghai Jiao Tong University School of MedicineState Key Laboratory of Bioreactor Engineering, Shanghai Key Laboratory of New Drug Design, East China University of Science and TechnologyAbstract 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.https://doi.org/10.1038/s41419-021-03653-4
collection	DOAJ
language	English
format	Article
sources	DOAJ
author	Keting Bao Yongyun Li Jinlian Wei Ruoxi Li Jie Yang Jiahao Shi Baoli Li Jin Zhu Fei Mao Renbing Jia Jian Li
spellingShingle	Keting Bao Yongyun Li Jinlian Wei Ruoxi Li Jie Yang Jiahao Shi Baoli Li Jin Zhu Fei Mao Renbing Jia Jian Li Fangchinoline suppresses conjunctival melanoma by directly binding FUBP2 and inhibiting the homologous recombination pathway Cell Death and Disease
author_facet	Keting Bao Yongyun Li Jinlian Wei Ruoxi Li Jie Yang Jiahao Shi Baoli Li Jin Zhu Fei Mao Renbing Jia Jian Li
author_sort	Keting Bao
title	Fangchinoline suppresses conjunctival melanoma by directly binding FUBP2 and inhibiting the homologous recombination pathway
title_short	Fangchinoline suppresses conjunctival melanoma by directly binding FUBP2 and inhibiting the homologous recombination pathway
title_full	Fangchinoline suppresses conjunctival melanoma by directly binding FUBP2 and inhibiting the homologous recombination pathway
title_fullStr	Fangchinoline suppresses conjunctival melanoma by directly binding FUBP2 and inhibiting the homologous recombination pathway
title_full_unstemmed	Fangchinoline suppresses conjunctival melanoma by directly binding FUBP2 and inhibiting the homologous recombination pathway
title_sort	fangchinoline suppresses conjunctival melanoma by directly binding fubp2 and inhibiting the homologous recombination pathway
publisher	Nature Publishing Group
series	Cell Death and Disease
issn	2041-4889
publishDate	2021-04-01
description	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.
url	https://doi.org/10.1038/s41419-021-03653-4
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Fangchinoline suppresses conjunctival melanoma by directly binding FUBP2 and inhibiting the homologous recombination pathway

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