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

Research output: Contribution to journalArticle

31 Citations (Scopus)

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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MicroRNAs
Urinary Bladder Neoplasms
Epigenomics
Neoplasms
DNA Methylation
Transcriptome
Transgenic Mice
Urinary Bladder
Up-Regulation
Biomarkers
Carcinoma
Growth
Genes

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Palmbos, P. L., Wang, L., Yang, H., Wang, Y., Leflein, J., Ahmet, M. L., ... 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

ATDC/TRIM29 drives invasive bladder cancer formation through miRNA-mediated and epigenetic mechanisms. / Palmbos, Phillip L.; Wang, Lidong; Yang, Huibin; Wang, Yin; Leflein, Jacob; Ahmet, McKenzie L.; Wilkinson, John E.; Kumar-Sinha, Chandan; Ney, Gina M.; Tomlins, Scott A.; Daignault, Stephanie; Kunju, Lakshmi P.; Wu, Xue Ru; Lotan, Yair; Liebert, Monica; Ljungman, Mats E.; Simeone, Diane M.

In: Cancer Research, Vol. 75, No. 23, 01.12.2015, p. 5155-5166.

Research output: Contribution to journalArticle

Palmbos, PL, Wang, L, Yang, H, Wang, Y, Leflein, J, Ahmet, ML, Wilkinson, JE, Kumar-Sinha, C, Ney, GM, Tomlins, SA, Daignault, S, Kunju, LP, Wu, XR, Lotan, Y, Liebert, M, Ljungman, ME & Simeone, DM 2015, 'ATDC/TRIM29 drives invasive bladder cancer formation through miRNA-mediated and epigenetic mechanisms', Cancer Research, vol. 75, no. 23, pp. 5155-5166. https://doi.org/10.1158/0008-5472.CAN-15-0603
Palmbos, Phillip L. ; Wang, Lidong ; Yang, Huibin ; Wang, Yin ; Leflein, Jacob ; Ahmet, McKenzie L. ; Wilkinson, John E. ; Kumar-Sinha, Chandan ; Ney, Gina M. ; Tomlins, Scott A. ; Daignault, Stephanie ; Kunju, Lakshmi P. ; Wu, Xue Ru ; Lotan, Yair ; Liebert, Monica ; Ljungman, Mats E. ; Simeone, Diane M. / ATDC/TRIM29 drives invasive bladder cancer formation through miRNA-mediated and epigenetic mechanisms. In: Cancer Research. 2015 ; Vol. 75, No. 23. pp. 5155-5166.
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