Upregulated SMYD3 promotes bladder cancer progression by targeting BCLAF1 and activating autophagy
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The recent discovery of a large number of histone methyltransferases reveals important roles of these enzymes in regulating tumor development and progression. SMYD3, a histone methyltransferase, is associated with poor prognosis of patients with prostate and gastric cancer. In the study, we attempted to investigate its putative oncogenic role on bladder cancer. Here, we report that SMYD3 frequently amplified in bladder cancer is correlated with bladder cancer progression and poor prognosis. Overexpression of SMYD3 promotes bladder cancer cell proliferation and invasion, whereas SMYD3 knockdown inhibits cancer cell growth and invasion. Mechanically, SMYD3 positively regulates the expression of BCL2-associated transcription factor 1 (BCLAF1). SMYD3 physically interacts with the promoter of BCLAF1 and upregulates its expression by accumulating di- and trimethylation of H3K4 at the BCLAF1 locus. We further show that SMYD3 overexpression in bladder cancer cells promotes autophagy activation, whereas BCLAF1 depletion inhibits SMYD3-induced autophagy. Finally, we demonstrate that SMYD3 promotes bladder cancer progression, at least in part by increasing BCLAF1 expression and activating autophagy. Our results establish a function for SMYD3 in autophagy activation and bladder cancer progression and suggest its candidacy as a new prognostic biomarker and target for clinical management of bladder cancer.
KeywordsSMYD3 BCLAF1 Autophagy Bladder cancer Histone methyltransferases
Non-muscle-invasive or superficial bladder cancer
Muscle invasive bladder cancer
Histone H3 lysine 4
SET and MYND domain containing protein 3
Normal human urothelial
BCL2-associated transcription factor 1
Authors’ Contribution statement
Planned experiments: Y F; Performed experiments: B S, M-y T, X-y M, Y Q, F Z, Y L; Analyzed data: Y F, B S; Contributed reagents or other essential material: F Z, Y L; Wrote the paper: Y F.
This work was funded by National Science Foundation of China (Grant No. 81402086).
Conflicts of interest
- 6.Kim WJ, Kim EJ, Kim SK, Kim YJ, Ha YS, Jeong P, Kim MJ, Yun SJ, Lee KM, Moon SK, Lee SC, Cha EJ, Bae SC: Predictive value of progression-related gene classifier in primary non-muscle invasive bladder cancer. Mol Cancer. 2010;9:3.Google Scholar
- 23.Kapinas K, Kessler CB, Ricks T, Gronowicz G, Delany AM: Mir-29 modulates wnt signaling in human osteoblasts through a positive feedback loop. J Biol Chem. 2010;285:25221-31.Google Scholar
- 30.Varier RA, Timmers HT. Histone lysine methylation and demethylation pathways in cancer. Biochim Biophys Acta. 1815;2011:75–89.Google Scholar