title: Upregulated SMYD3 promotes bladder cancer progression by targeting BCLAF1 and activating autophagy.
abstract: 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.
authors.affiliation: Department of Renal Transplantation and Urology, Shanghai First People's Hospital, Shanghai Jiaotong University, 100 Haining Road, Shanghai, 200080, China.
authors.forename: Bing
authors.initials: B
authors.lastname: Shen
authors.affiliation: Department of Renal Transplantation and Urology, Shanghai First People's Hospital, Shanghai Jiaotong University, 100 Haining Road, Shanghai, 200080, China.
authors.forename: Mingyue
authors.initials: M
authors.lastname: Tan
authors.affiliation: Department of Renal Transplantation and Urology, Shanghai First People's Hospital, Shanghai Jiaotong University, 100 Haining Road, Shanghai, 200080, China.
authors.forename: Xinyu
authors.initials: X
authors.lastname: Mu
authors.affiliation: Department of Renal Transplantation and Urology, Shanghai First People's Hospital, Shanghai Jiaotong University, 100 Haining Road, Shanghai, 200080, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Qin
authors.affiliation: Department of Renal Transplantation and Urology, Shanghai First People's Hospital, Shanghai Jiaotong University, 100 Haining Road, Shanghai, 200080, China.
authors.forename: Fang
authors.initials: F
authors.lastname: Zhang
authors.affiliation: Department of Renal Transplantation and Urology, Shanghai First People's Hospital, Shanghai Jiaotong University, 100 Haining Road, Shanghai, 200080, China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Renal Transplantation and Urology, Shanghai First People's Hospital, Shanghai Jiaotong University, 100 Haining Road, Shanghai, 200080, China. fanyu1965@163.com.
authors.forename: Yu
authors.initials: Y
authors.lastname: Fan
mesh_terms: D000368:Aged; D001343:Autophagy / Q000235:genetics*; D002295:Carcinoma, Transitional Cell / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D045744:Cell Line, Tumor; D018450:Disease Progression; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D042421:Histone Code / Q000235:genetics*; D011495:Histone-Lysine N-Methyltransferase / Q000502:physiology*; D006657:Histones / Q000378:metabolism; D006801:Humans; D008297:Male; D008745:Methylation; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D011379:Prognosis; D011401:Promoter Regions, Genetic / Q000235:genetics; D011499:Protein Processing, Post-Translational / Q000235:genetics; D034622:RNA Interference; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D012097:Repressor Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D025521:Tumor Suppressor Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D001749:Urinary Bladder Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology
chemical_list: C119386:BCLAF1 protein, human; D006657:Histones; D009363:Neoplasm Proteins; D011993:Recombinant Fusion Proteins; D012097:Repressor Proteins; D025521:Tumor Suppressor Proteins; D011495:Histone-Lysine N-Methyltransferase; C506278:SMYD3 protein, human
keywords: Autophagy; BCLAF1; Bladder cancer; Histone methyltransferases; SMYD3