Zhu Liangsong, Wang Jianfeng, Kong Wen, Huang Jiwei, Dong Baijun, Huang Yiran, Xue Wei, Zhang Jin
Department of Urology, Ren Ji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200127, China.
Acta Pharm Sin B. 2019 Mar;9(2):324-334. doi: 10.1016/j.apsb.2018.10.006. Epub 2018 Oct 30.
Histone lysine-specific demethylase 1 (LSD1) has been implicated in the disease progression of several types of solid tumors. This study provides the first evidence showing that LSD1 overexpression occurred in 62.6% (224/358) of clear cell renal cell carcinomas (ccRCC). LSD1 expression was associated with the progression of ccRCC, as indicated by TNM stage (=0.006), especially tumor stage (=0.017) and lymph node metastasis (=0.030). High LSD1 expression proved to be an independent prognostic factor for poor overall survival (<0.001) and recurrence-free survival (<0.001) of ccRCC patients. We further show that LSD1 inhibition by siRNA knockdown or using the small molecule inhibitor SP2509 suppressed the growth of ccRCC and . Mechanistically, inhibition of LSD1 decreased the H3K4 demethylation at the gene promoter, which was associated with P21 upregulation and cell cycle arrest at G1/S in ccRCC cells. Our findings provide new mechanistic insights into the role of LSD1 in ccRCC and suggest the therapeutic potential of LSD1 inhibitors in ccRCC treatment.
组蛋白赖氨酸特异性去甲基化酶1（LSD1）与多种实体瘤的疾病进展有关。本研究首次证明，62.6%（224/358）的透明细胞肾细胞癌（ccRCC）中存在LSD1过表达。LSD1表达与ccRCC的进展相关，如TNM分期（=0.006）所示，尤其是肿瘤分期（=0.017）和淋巴结转移（=0.030）。高LSD1表达被证明是ccRCC患者总生存期差（<0.001）和无复发生存期差（<0.001）的独立预后因素。我们进一步表明，通过siRNA敲低或使用小分子抑制剂SP2509抑制LSD1可抑制ccRCC的生长。从机制上讲，抑制LSD1可降低基因启动子处的H3K4去甲基化，这与ccRCC细胞中P21上调和G1/S期细胞周期阻滞有关。我们的研究结果为LSD1在ccRCC中的作用提供了新的机制见解，并提示LSD1抑制剂在ccRCC治疗中的治疗潜力。
