title: ATDC/TRIM29 Drives Invasive Bladder Cancer Formation through miRNA-Mediated and Epigenetic Mechanisms.
abstract: Bladder cancer is a common and deadly malignancy but its treatment has advanced little due to poor understanding of the factors and pathways that promote disease. ATDC/TRIM29 is a highly expressed gene in several lethal tumor types, including bladder tumors, but its role as a pathogenic driver has not been established. Here we show that overexpression of ATDC in vivo is sufficient to drive both noninvasive and invasive bladder carcinoma development in transgenic mice. ATDC-driven bladder tumors were indistinguishable from human bladder cancers, which displayed similar gene expression signatures. Clinically, ATDC was highly expressed in bladder tumors in a manner associated with invasive growth behaviors. Mechanistically, ATDC exerted its oncogenic effects by suppressing miR-29 and subsequent upregulation of DNMT3A, leading to DNA methylation and silencing of the tumor suppressor PTEN. Taken together, our findings established a role for ATDC as a robust pathogenic driver of bladder cancer development, identified downstream effector pathways, and implicated ATDC as a candidate biomarker and therapeutic target.
authors.affiliation: Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor, Michigan. Translational Oncology Program, University of Michigan Medical Center, Ann Arbor, Michigan.
authors.forename: Phillip L
authors.initials: PL
authors.lastname: Palmbos
authors.affiliation: Translational Oncology Program, University of Michigan Medical Center, Ann Arbor, Michigan. Department of Surgery, University of Michigan Medical Center, Ann Arbor, Michigan.
authors.forename: Lidong
authors.initials: L
authors.lastname: Wang
authors.affiliation: Translational Oncology Program, University of Michigan Medical Center, Ann Arbor, Michigan. Department of Surgery, University of Michigan Medical Center, Ann Arbor, Michigan.
authors.forename: Huibin
authors.initials: H
authors.lastname: Yang
authors.affiliation: Translational Oncology Program, University of Michigan Medical Center, Ann Arbor, Michigan. Department of Surgery, University of Michigan Medical Center, Ann Arbor, Michigan.
authors.forename: Yin
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Translational Oncology Program, University of Michigan Medical Center, Ann Arbor, Michigan. Department of Surgery, University of Michigan Medical Center, Ann Arbor, Michigan.
authors.forename: Jacob
authors.initials: J
authors.lastname: Leflein
authors.affiliation: Translational Oncology Program, University of Michigan Medical Center, Ann Arbor, Michigan. Department of Surgery, University of Michigan Medical Center, Ann Arbor, Michigan.
authors.forename: McKenzie L
authors.initials: ML
authors.lastname: Ahmet
authors.affiliation: Department of Pathology, University of Michigan Medical Center, Ann Arbor, Michigan. Department of Laboratory Animal Medicine, University of Michigan Medical Center, Ann Arbor, Michigan.
authors.forename: John E
authors.initials: JE
authors.lastname: Wilkinson
authors.affiliation: Department of Pathology, University of Michigan Medical Center, Ann Arbor, Michigan.
authors.forename: Chandan
authors.initials: C
authors.lastname: Kumar-Sinha
authors.affiliation: Translational Oncology Program, University of Michigan Medical Center, Ann Arbor, Michigan. Department of Pediatrics, University of Michigan Medical Center, Ann Arbor, Michigan.
authors.forename: Gina M
authors.initials: GM
authors.lastname: Ney
authors.affiliation: Department of Pathology, University of Michigan Medical Center, Ann Arbor, Michigan.
authors.forename: Scott A
authors.initials: SA
authors.lastname: Tomlins
authors.affiliation: Department of Biostatistics, University of Michigan Medical Center, Ann Arbor, Michigan.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Daignault
authors.affiliation: Department of Pathology, University of Michigan Medical Center, Ann Arbor, Michigan.
authors.forename: Lakshmi P
authors.initials: LP
authors.lastname: Kunju
authors.affiliation: Departments of Urology and Pathology and Veterans Affairs Medical Center in Manhattan, New York University School of Medicine, New York, New York.
authors.forename: Xue-Ru
authors.initials: XR
authors.lastname: Wu
authors.affiliation: Department of Urology, University of Texas Southwestern Medical Center, Dallas, Texas.
authors.forename: Yair
authors.initials: Y
authors.lastname: Lotan
authors.affiliation: Translational Oncology Program, University of Michigan Medical Center, Ann Arbor, Michigan. Department of Urology, University of Michigan Medical Center, Ann Arbor, Michigan.
authors.forename: Monica
authors.initials: M
authors.lastname: Liebert
authors.affiliation: Translational Oncology Program, University of Michigan Medical Center, Ann Arbor, Michigan. Department of Radiation Oncology, University of Michigan Medical Center, Ann Arbor, Michigan.
authors.forename: Mats E
authors.initials: ME
authors.lastname: Ljungman
authors.affiliation: Translational Oncology Program, University of Michigan Medical Center, Ann Arbor, Michigan. Department of Surgery, University of Michigan Medical Center, Ann Arbor, Michigan. Department of Molecular and Integrative Physiology, University of Michigan Medical Center, Ann Arbor, Michigan. simeone@med.umich.edu.
authors.forename: Diane M
authors.initials: DM
authors.lastname: Simeone
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics / Q000378:metabolism; D000090205:DNA Methyltransferase 3A; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics*; D004195:Disease Models, Animal; D044127:Epigenesis, Genetic; D005260:Female; D015870:Gene Expression; D006801:Humans; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D009361:Neoplasm Invasiveness; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics*; D014162:Transfection; D015854:Up-Regulation; D001749:Urinary Bladder Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology
chemical_list: D004268:DNA-Binding Proteins; C000717967:DNMT3A protein, human; C000715535:Dnmt3a protein, mouse; D035683:MicroRNAs; C087296:TRIM29 protein, human; C550082:TRIM29 protein, mouse; D014157:Transcription Factors; D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; C487757:Pten protein, mouse