Bromodomain protein BRD4 inhibitor JQ1 regulates potential prognostic molecules in advanced renal cell carcinoma
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Takashi Sakaguchi1,*, Hirofumi Yoshino1,*, Satoshi Sugita1, Kazutaka Miyamoto1, Masaya Yonemori1, Yoichi Osako1, Makiko Meguro-Horike2, Shin-Ichi Horike2, Masayuki Nakagawa1 and Hideki Enokida1
1Department of Urology, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan
2Division of Functional Genomics, Advanced Science Research Center, Kanazawa University, Kanazawa, Japan
*These authors contributed equally to this work
Hideki Enokida, email: [email protected]kufm.kagoshima-u.ac.jp
Keywords: bromodomain; BRD4; JQ1; sunitinib resistance; renal cell carcinoma
Received: January 16, 2018 Accepted: April 05, 2018 Published: May 01, 2018
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 BRD4 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 SCG5, SPOCD1, RGS19, and ARHGAP22 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 SCG5, SPOCD1, RGS19, and ARHGAP22 as potential prognostic markers and showed that BRD4 inhibition may have applications as a potential therapeutic approach in sunitinib-sensitive and -resistant ccRCC.
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