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

Keting Bao,Jie Yang,Ruoxi Li,Renbing Jia,Jiahao Shi,Yongyun Li,Jin Zhu,Jian Li,Fei Mao,Baoli Li,Jinlian Wei

doi:10.1038/s41419-021-03653-4

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.

Highlights

Conjunctival melanoma (CM) is a rare and fatal ocular tumour that accounts for ~2% of all ocular malignancies[1] and 1.6% of all non-cutaneous melanomas[2]
We assessed the anti-proliferative activity of fangchinoline against three other CM cell lines obtained from Caucasian patients with a typical NRAS (CRMM2) or BRAF mutation (CRMM1 and CM2005.1)[26,27]
There were no differences in the levels of alanine transaminase (ALT), aspartate transaminase (AST), creatinine or urea in mice serum of the fangchinoline-treated and control groups, indicating that fangchinoline does not have an impact on liver and renal functions (Supplementary Fig. S1)

Summary

Introduction

Conjunctival melanoma (CM) is a rare and fatal ocular tumour that accounts for ~2% of all ocular malignancies[1] and 1.6% of all non-cutaneous melanomas[2]. CM is more common in the Caucasian population (annual incidence of 0.2–0.5 per million3) compared to the Asian population (annual incidence of 0.15 per million[4]). The first-line treatment patients in a Dutch referral centre, the overall 5-year recurrence rate, metastasis rate and melanoma-related survival rate were reported to be 29%, 12% and 90%, respectively[10]. In another study on Chinese CM patients, the 10-year tumour-related recurrence rate, metastasis rate and mortality were observed to be 66%, 51% and 37%, respectively.

Methods

Results

Conclusion