ATDC/TRIM29 drives invasive bladder cancer formation through miRNA-mediated and epigenetic mechanisms

Phillip L. Palmbos, Lidong Wang, Huibin Yang, Yin Wang, Jacob Leflein, McKenzie L. Ahmet, John E. Wilkinson, Chandan Kumar-Sinha, Gina M. Ney, Scott A. Tomlins, Stephanie Daignault, Lakshmi P. Kunju, Xue Ru Wu, Yair Lotan, Monica Liebert, Mats E. Ljungman, Diane M. Simeone

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38 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)5155-5166
Number of pages12
JournalCancer research
Volume75
Issue number23
DOIs
StatePublished - Dec 1 2015

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ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Palmbos, P. L., Wang, L., Yang, H., Wang, Y., Leflein, J., Ahmet, M. L., Wilkinson, J. E., Kumar-Sinha, C., Ney, G. M., Tomlins, S. A., Daignault, S., Kunju, L. P., Wu, X. R., Lotan, Y., Liebert, M., Ljungman, M. E., & Simeone, D. M. (2015). ATDC/TRIM29 drives invasive bladder cancer formation through miRNA-mediated and epigenetic mechanisms. Cancer research, 75(23), 5155-5166. https://doi.org/10.1158/0008-5472.CAN-15-0603