SMYD3 as a Poor Prognostic Indicator Promotes Tumorigenic Phenotypes and Progression of Bladder Cancer via Direct Activation of IGF-1R/AKT/mTOR Signaling Pathway
AKT/mTOR pathway is critical for bladder cancer (BC) and is aberrantly activated during BC progression. However, few studies have addressed the epigenetic regulation AKT/mTOR signaling. SET and MYND domain-containing protein 3 (SMYD3) is a histone methyltransferase that targets histone H3-K4 for di/trimethylation. In the present study, we determine the role and the underlying mechanism of SMYD3 in the pathogenesis of BC.
The expression of SMYD3 was examined via Western blot, real-time PCR and immunohistochemistry in a cohort of BC tissues. A series of in vivo and in vitro assays was performed to elucidate the contribution and underlying mechanism of the SMYD3/ IGF-1R (insulin-like growth factor-1 receptor)/AKT axis in BC phenotypes and progression.
Strong SMYD3 expression was detected in BC tumors, while normal bladder tissues only showed weak or undetectable signals. The level of SMYD3 expression was positively correlated with tumor stage, lymph node metastasis, histological grade, and poor survival. Depletion of SMYD3 inhibited BC cell proliferation, colony formation, migration, invasion, and xenograft tumor growth. Mechanistically, SMYD3 inhibition abolished the activity of the AKT/mTOR pathway, thereby triggering multiple negative effects on BC cells. Furthermore, SMYD3 activates the expression of IGF-1R, a critical activator of AKT, via inducing hyper-methylation of histone H3-K4 and subsequent chromatin remodeling in the IGF-1R promoter region. Two functional SMYD3-binding motifs were identified.
Our findings suggest that IGF-1R is a new target gene of SMYD3, and by stimulating IGF-1R transcription, SMYD3 activates the AKT/mTOR pathway, thereby contributing to BC development and progression.
Funding: The study was funded by the National Natural Science Foundation of China (Nos.: 81711530048, 81372765?81572515, 81472395, 81672522); Shandong Provincial Natural Science Foundation, China (No: ZR2011HM055, ZR2014HQ035, BS2014YY036); Research fund of Shandong University Qilu Hospital (2014QLKY16)