Sakaguchi Takashi, Yoshino Hirofumi, Sugita Satoshi, Miyamoto Kazutaka, Yonemori Masaya, Osako Yoichi, Meguro-Horike Makiko, Horike Shin-Ichi, Nakagawa Masayuki, Enokida Hideki
Department of Urology, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan.
Division of Functional Genomics, Advanced Science Research Center, Kanazawa University, Kanazawa, Japan.
Oncotarget. 2018 May 1;9(33):23003-23017. doi: 10.18632/oncotarget.25190.
Sunitinib is a standard molecular-targeted drug used as a first-line treatment for metastatic clear cell renal cell carcinoma (ccRCC); however, resistance to sunitinib has become a major problem in medical practice. Recently, bromodomain containing 4 (BRD4), a member of the bromodomain family proteins, was identified as a promising therapeutic target, and its inhibitor JQ1 has been shown to have inhibitory effects in various human cancers. However, the anti-cancer effects of JQ1 in ccRCC, particularly sunitinib-resistant ccRCC, are still unclear. Here, we aimed to elucidate the anti-cancer effects of JQ1 and the mechanisms underlying BRD4 inhibition in sunitinib-sensitive and -resistant ccRCCs. Analysis of The Cancer Genome Atlas (TCGA) ccRCC cohort showed that patients with high expression had shorter overall survival than those with low expression. JQ1 treatment significantly inhibited tumor growth of sunitinib-sensitive and -resistant ccRCC cells in part through MYC regulation. Based on RNA sequencing analyses of ccRCC cells treated with JQ1 to elucidate the mechanisms other than MYC regulation, we identified several oncogenes that may be potential therapeutic targets or prognostic markers; patients with high expression of , , , and had poorer overall survival than those with low expression in TCGA ccRCC cohort. Chromatin immunoprecipitation assays revealed that these oncogenes may be promising BRD4 targets, particularly in sunitinib-resistant ccRCC cells. These results identified , and as potential prognostic markers and showed that BRD4 inhibition may have applications as a potential therapeutic approach in sunitinib-sensitive and -resistant ccRCC.
舒尼替尼是一种标准的分子靶向药物，用作转移性透明细胞肾细胞癌（ccRCC）的一线治疗药物；然而，对舒尼替尼的耐药性已成为医学实践中的一个主要问题。最近，含溴结构域蛋白4（BRD4），作为溴结构域家族蛋白的一员，被确定为一个有前景的治疗靶点，其抑制剂JQ1已被证明在多种人类癌症中具有抑制作用。然而，JQ1在ccRCC，特别是舒尼替尼耐药的ccRCC中的抗癌作用仍不清楚。在这里，我们旨在阐明JQ1的抗癌作用以及BRD4抑制在舒尼替尼敏感和耐药ccRCC中的潜在机制。对癌症基因组图谱（TCGA）ccRCC队列的分析表明，高表达患者的总生存期比低表达患者短。JQ1治疗部分通过MYC调控显著抑制了舒尼替尼敏感和耐药ccRCC细胞的肿瘤生长。基于对用JQ1处理的ccRCC细胞进行RNA测序分析以阐明除MYC调控之外的机制，我们鉴定了几个可能是潜在治疗靶点或预后标志物的癌基因；在TCGA ccRCC队列中，、、和高表达的患者总生存期比低表达患者差。染色质免疫沉淀试验表明，这些癌基因可能是有前景的BRD4靶点，特别是在舒尼替尼耐药的ccRCC细胞中。这些结果确定了和为潜在的预后标志物，并表明BRD4抑制可能作为一种潜在的治疗方法应用于舒尼替尼敏感和耐药的ccRCC。
