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

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.

SMYD3 promotes colon adenocarcinoma (COAD) progression by mediating cell proliferation and apoptosis

“…SMYD1 has been reported to be associated with several solid tumors, including breast cancer (40). Additionally, SMYD2 exhibited high expression in multiple types of tumors, including gastric cancer and colorectal cancer, and affected the migration and invasion of tumor cells (41,42). Combined with the results of the current study, we hypothesized that the development of inhibitors targeting SMYD family proteins has potential advantages for cancer targeted therapy.…”

Sirtuin 6 regulates the proliferation and survival of clear cell renal cell carcinoma cells via B‑cell lymphoma 2

“…Molecular mechanisms that disrupt these pre-apoptotic signals are thought to be responsible for tumor resistance to chemotherapy ( 28 ). Thus, cisplatin has been the standard experimental drug to study the molecular mechanism of chemosensitivity in renal cell carcinoma ( 29 – 31 ). In accordance with these observations, the results of the present study demonstrated that high SIRT6 expression was associated with poor prognosis of patients with ccRCC, and SIRT6 knockdown decreased the proliferative, migratory and invasive abilities of ccRCC cells, and enhanced their sensitivity to cisplatin.…”

Epigenetic Alterations in Renal Cell Cancer With TKIs Resistance: From Mechanisms to Clinical Applications

“…The Wnt/β-catenin pathway acts as one of the signaling pathways controlling EMT through directly or indirectly targeting several key transcription factors regulating E-cadherin expression and/or the fate of other epithelial molecules ( Valenta et al, 2012 ). SET and MYND domain-containing protein 2 (SMYD2), which acts as one of the SMYD-methyltransferase protein family and specifically methylates H3K4 through its SET domain ( Abu-Farha et al, 2008 ), is deemed to regulate the expression of miR-125b ( Yan et al, 2019 ). miR-125b bind directly to the 3'-UTR of DKK3, a key regulatory factor in the Wnt/β-catenin pathway which acts as a tumor suppressor in RCC ( Lu et al, 2017 ).…”

“…miR-125b bind directly to the 3'-UTR of DKK3, a key regulatory factor in the Wnt/β-catenin pathway which acts as a tumor suppressor in RCC ( Lu et al, 2017 ). Thus, the activation of SMYD2/miRNA-EMT pathway weakens the effect sunitinib treatment and accelerates the tumor growth ( Yan et al, 2019 ).…”