The Role of BPTF in Melanoma Progression and in Response to BRAF-Targeted Therapy
The Role of BPTF in Melanoma Progression and in Response to BRAF-Targeted Therapy
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DOI：
10.1093/jnci/djv034
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发表时间：
2015-05-01
影响因子：
10.3
通讯作者：
Kashani-Sabet, Mohammed
中科院分区：
文献类型：
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作者：
Dar, Altaf A.;Nosrati, Mehdi;Kashani-Sabet, Mohammed
背景资料：溴结构域PHD指转录因子（BPTF）在染色质重塑中起重要作用，但其在肿瘤进展中的功能作用尚不完全清楚。在这里，我们探讨了BPTF在melanoma.Methods中的致癌作用：BPTF的差异表达的后果进行了探讨，在几个黑色素瘤细胞系中使用shRNA介导的敲低。免疫印迹法用于评估由BPTF调节的各种蛋白质的表达。使用集落形成、侵袭、细胞周期、对选择性BRAF抑制剂的敏感性的测定以及在黑素瘤进展的异种移植模型中研究BPTF在黑素瘤进展中的功能作用（n = 12只小鼠/组）。BPTF在黑色素瘤进展中的生物标志物作用采用荧光原位杂交和免疫组织化学分析进行评估。结果：shRNA介导的BPTF沉默抑制了黑色素瘤细胞的增殖能力（65.5%）和转移能力（66.4%）。在77例黑色素瘤中的28例（36.4%）中观察到BPTF拷贝数升高（平均值= 3）。BPTF过表达预测了311例黑色素瘤患者的不良生存率（无远处转移生存率P = 0.03，疾病特异性生存率P = 0.008），并促进了黑色素瘤细胞系对BRAF抑制剂的耐药性。转移性黑色素瘤肿瘤进展BRAF抑制剂含有低BPTF表达，凋亡肿瘤细胞亚克隆，表明肿瘤内的药物反应性亚克隆的持续存在，表现出整体耐药性antiBRAF agents.Conclusions：这些研究表明多protumorigenic功能BPTF，并确定它作为一个新的抗癌治疗目标。他们还建议BPTF靶向与BRAF抑制剂的组合作为具有突变BRAF的黑色素瘤的新型治疗策略。
Background: Bromodomain PHD finger transcription factor (BPTF) plays an important role in chromatin remodeling, but its functional role in tumor progression is incompletely understood. Here we explore the oncogenic effects of BPTF in melanoma.Methods: The consequences of differential expression of BPTF were explored using shRNA-mediated knockdown in several melanoma cell lines. Immunoblotting was used to assess the expression of various proteins regulated by BPTF. The functional role of BPTF in melanoma progression was investigated using assays of colony formation, invasion, cell cycle, sensitivity to selective BRAF inhibitors, and in xenograft models of melanoma progression (n = 12 mice per group). The biomarker role of BPTF in melanoma progression was assessed using fluorescence in situ hybridization and immunohistochemical analyses. All statistical tests were two-sided.Results: shRNA-mediated BPTF silencing suppressed the proliferative capacity (by 65.5%) and metastatic potential (by 66.4%) of melanoma cells. Elevated BPTF copy number (mean = 3) was observed in 28 of 77 (36.4%) melanomas. BPTF overexpression predicted poor survival in a cohort of 311 melanoma patients (distant metastasis-free survival P = .03, and disease-specific survival P = .008), and promoted resistance to BRAF inhibitors in melanoma cell lines. Metastatic melanoma tumors progressing on BRAF inhibitors contained low BPTF-expressing, apoptotic tumor cell subclones, indicating the continued presence of drug-responsive subclones within tumors demonstrating overall resistance to antiBRAF agents.Conclusions: These studies demonstrate multiple protumorigenic functions for BPTF and identify it as a novel target for anticancer therapy. They also suggest the combination of BPTF targeting with BRAF inhibitors as a novel therapeutic strategy for melanomas with mutant BRAF.