Liu Weiqin, Cui Zedu, Wan Qi, Liu Ying, Chen Minghao, Cheng Yaqi, Sang Xuan, Su Yaru, Gu Simin, Li Chaoyang, Liu Chang, Chen Shuxia, Wang Zhichong, Wang Xiaoran
State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat- Sen University, Guangdong Provincial Key Laboratory of Ophthalmology Visual Science, Guangzhou 510060, China; Guangdong Provincial Clinical Research Center for Ocular Diseases, Guangzhou 510060, China.
State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat- Sen University, Guangdong Provincial Key Laboratory of Ophthalmology Visual Science, Guangzhou 510060, China; Guangdong Provincial Clinical Research Center for Ocular Diseases, Guangzhou 510060, China; West China Hospital of Sichuan University, 610041 Chengdu, China.
Cell Signal. 2025 Jan;125:111483. doi: 10.1016/j.cellsig.2024.111483. Epub 2024 Oct 22.
Uveal melanoma (UM), the most common adult ocular tumor, is aggressive and resistant to treatment, posing threat to patients' lives. The novel, effective therapies and the exploration of chemosensitizer for UM are imperative. The anticancer efficacy was evaluated with and without JQ1 treatment or ABCB5 gene silencing or overexpression. RNA sequencing identified downstream effectors in JQ1-treated cells. Integrated analysis of The Cancer Genome Atlas data (TCGA) and immunohistochemistry (IHC) revealed the oncogenic role of ABCB5. Functional analyses of JQ1 and defective ABCB5 were conducted using flow cytometry, transmission electron microscopy (TEM), IHC and western blot. The effects of JQ1 were validated in a heterotopic tumor model derived from OCM-1 cells. JQ1 inhibited cell proliferation, migration and invasion, induced cell cycle arrest and promoted apoptosis. JQ1 also suppressed the survival of UM in heterotopic tumor model. RNA sequencing indicated that JQ1 down-regulated the expressions of ABCB5 and autophagy-related genes, which was confirmed in vitro and in vivo by western blot. ABCB5, a marker associated with cancer stem cells and chemo-resistance, exhibited heightened expression in UM tissues, linked to immune infiltration. Notably, disrupting ABCB5 expression impeded UM cell proliferation and interfered with autophagy. Moreover, the overexpression of ABCB5 promoted cell proliferation, migration and invasion, and rescued autophagy related gene expression. Of note, JQ1 enhanced the sensitivity of OCM-1 cells to chemotherapy. Thus JQ1 inhibits UM survival via ABCB5-mediated autophagy and enhances chemo-sensitivity, suggesting potential for BET-based approaches in UM clinical management.
葡萄膜黑色素瘤（UM）是最常见的成人眼部肿瘤，具有侵袭性且对治疗耐药，对患者生命构成威胁。因此，迫切需要开发针对UM的新型有效疗法并探索化学增敏剂。通过有或无JQ1处理、ABCB5基因沉默或过表达来评估抗癌疗效。RNA测序确定了JQ1处理细胞中的下游效应物。对癌症基因组图谱数据（TCGA）和免疫组织化学（IHC）进行综合分析，揭示了ABCB5的致癌作用。使用流式细胞术、透射电子显微镜（TEM）、IHC和蛋白质印迹法对JQ1和缺陷型ABCB5进行功能分析。在源自OCM-1细胞的异位肿瘤模型中验证了JQ1的作用。JQ1抑制细胞增殖、迁移和侵袭，诱导细胞周期停滞并促进细胞凋亡。JQ1还抑制了异位肿瘤模型中UM的存活。RNA测序表明，JQ1下调了ABCB5和自噬相关基因的表达，蛋白质印迹法在体外和体内均证实了这一点。ABCB5是一种与癌症干细胞和化疗耐药相关的标志物，在UM组织中表达升高，与免疫浸润有关。值得注意的是，破坏ABCB5的表达会阻碍UM细胞增殖并干扰自噬。此外，ABCB5的过表达促进细胞增殖、迁移和侵袭，并挽救自噬相关基因的表达。值得注意的是，JQ1增强了OCM-1细胞对化疗的敏感性。因此，JQ1通过ABCB5介导的自噬抑制UM存活并增强化疗敏感性，这表明基于BET的方法在UM临床管理中具有潜力。
