Inhibition of SMYD2 suppresses tumor progression by down-regulating microRNA-125b and attenuates multi-drug resistance in renal cell carcinoma

被引：61
作者：
Yan, Libin [1 ,2 ]
Ding, Beichen [1 ,3 ]
Liu, Haoran [1 ,2 ]
Zhang, Yangjun [1 ,2 ]
Zeng, Jin [1 ,2 ]
Hu, Junhui [1 ,2 ]
Yao, Weimin [1 ,2 ]
Yu, Gan [1 ,2 ]
An, Ruihua [3 ]
Chen, Zhiqiang [1 ,2 ]
Ye, Zhangqun [1 ,2 ]
Xing, Jinchun [4 ]
Xiao, Kefeng [5 ]
Wu, Lily [6 ]
Xu, Hua [1 ,2 ]
机构：
[1] Huazhong Univ Sci & Technol, Tongji Hosp, Tongji Med Coll, Dept Urol, Wuhan, Hubei, Peoples R China
[2] Inst Urol Hubei Prov, Wuhan, Hubei, Peoples R China
[3] Harbin Med Univ, Dept Urinary Surg, Affiliated Hosp 1, Harbin, Heilongjiang, Peoples R China
[4] Xiamen Univ, Dept Urol, Affiliated Hosp 1, Xiamen, Fujian, Peoples R China
[5] Peoples Hosp Shenzhen City, Dept Urol, Shenzhen, Peoples R China
[6] Univ Calif Los Angeles, David Geffen Sch Med, Dept Mol & Med Pharmacol, Los Angeles, CA 90095 USA
来源：
THERANOSTICS | 2019年 / 9卷 / 26期
基金：
中国国家自然科学基金;
关键词：
SMYD2; Renal cell carcinoma; MicroRNA; Multidrug resistance; HEPATOCELLULAR-CARCINOMA; POOR-PROGNOSIS; OVEREXPRESSION; METHYLATION; PROTEIN; CANCER; PROLIFERATION; METHYLTRANSFERASES; EXPRESSION; MALIGNANCY;
D O I：
10.7150/thno.37628
中图分类号：
R-3 [医学研究方法]; R3 [基础医学];
学科分类号：
1001 ;
摘要：
SMYD2 is a histone methyltransferase that has been reported to be an important epigenetic regulator. This study aims to investigate SMYD2 as a prognostic indicator of clear cell renal cell carcinoma (ccRCC) and explore its role in tumorigenesis and multi-drug resistance. Methods: Tumor specimens, clinicopathologic information, and prognostic outcomes of 186 ccRCC patients from three hospitals in China were collected for SMYD2 immunohistochemistry staining, Kaplan-Meier analysis, and Cox proportional hazards-regression analysis. MicroRNA (miRNA)-microarray profiling identified differentially expressed miRNAs in renal cancer cells subjected to SMYD2 knockdown or treatment with the SMYD2 inhibitor AZ505. The effects of SMYD2 and candidate SMYD2-mediated miRNAs on renal cancer cell proliferation, migration, clonogenicity, and tumorigenicity were determined via cell-function assays and murine xenograft experiments. The half-inhibitory concentrations (IC50) of five antineoplastic drugs (cisplatin, doxorubicin, fluorouracil, docetaxel, and sunitinib) in AZ505-treated and control cells were calculated, and the effects of SMYD2 inhibition on P-glycoprotein (P-gP) expression and multiple-drug resistance were verified. Results: SMYD2 was overexpressed and acted as an oncogene in ccRCC. High SMYD2 expression correlated with a high TNM stage (P = 0.007) and early tumor relapse (P = 0.032). SMYD2 independently predicted a worse overall survival (P = 0.022) and disease-free survival (P = 0.048). AZ505 inhibited the binding of SMYD2 to the miR-125b promoter region (based on chromatin immunoprecipitation assays) and suppressed ccRCC cell migration and invasion by inhibiting the SMYD2/miR-125b/DKK3 pathway. SMYD2 and miR-125b inhibition acted synergistically with anticancer drugs via P-gP suppression in vitro and in vivo. Conclusions: These findings suggested that SMYD2 plays an important role in ccRCC development and could be a potential biomarker for the treatment and prognosis of RCC.
引用
收藏
页码：8377 / 8391
页数：15
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