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

  • Theranostics. 2019 Oct 22;9(26):8377-8391. doi: 10.7150/thno.37628.
Libin Yan  1  2 ,  Beichen Ding  1  3 ,  Haoran Liu  1  2 ,  Yangjun Zhang  1  2 ,  Jin Zeng  1  2 ,  Junhui Hu  1  2 ,  Weimin Yao  1  2 ,  Gan Yu  1  2 ,  Ruihua An  3 ,  Zhiqiang Chen  1  2 ,  Zhangqun Ye  1  2 ,  Jinchun Xing  4 ,  Kefeng Xiao  5 ,  Lily Wu  6 ,  Hua Xu  1  2
Affiliations
  • 1. Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
  • 2. Institute of Urology of Hubei Province, Wuhan, China.
  • 3. Department of Urinary Surgery, First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China.
  • 4. Department of Urology, The First Affiliated Hospital of Xiamen University, Xiamen, China.
  • 5. Department of Urology, The People's Hospital of Shenzhen City, Shenzhen, China.
  • 6. Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, USA.
PMID: 31754403 DOI: 10.7150/thno.37628
Abstract

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.

Keywords
MicroRNA; Multidrug resistance; Renal cell carcinoma; SMYD2.
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