Cytoplasmic, full length and novel cleaved variant, TBLR1 reduces apoptosis in prostate cancer under androgen deprivation
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Garrett Daniels1, Xinmin Zhang2, Xuelin Zhong1, Larion Santiago1, Ling Hang Wang1, Xinyu Wu1, Jack Y. Zhang1, Fengxia Liang1, Xin Li3, Thomas A. Neubert4, Laurey Steinke5, Ying Shen1, Ross Basch1, Robert Schneider6, David E. Levy1, Peng Lee1,7,8,9
1Department of Pathology, New York University School of Medicine, New York, NY, USA
2Department of Pathology and Laboratory Medicine, Hofstra North Shore-LIJ School of Medicine, Hempstead, NY, USA
3Department of Basic Science and Craniofacial Biology, New York University College of Dentistry, New York, NY, USA
4Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, NY, USA
5Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA
6Department of Microbiology and Molecular Pathogenesis, New York University School of Medicine, New York, NY, USA
7Department of Urology, New York University School of Medicine, New York, NY, USA
8NYU Cancer Institute, New York University School of Medicine, New York, NY, USA
9New York Harbor Healthcare System, New York University School of Medicine, New York, NY, USA
Peng Lee, email: firstname.lastname@example.org
Keywords: prostate cancer, subcellular localization, castration resistance, TBLR1, cvTBLR1
Received: November 03, 2015 Accepted: March 28, 2016 Published: April 26, 2016
TBLR1/TBL1XR1, a core component of the nuclear receptor corepressor (NCoR) complex critical for the regulation of multiple nuclear receptors, is a transcriptional coactivator of androgen receptor (AR) and functions as a tumor suppressor when expressed in the nucleus in prostate. Subcellular localization of a protein is critical for its function, and although TBLR1, as a transcriptional cofactor, has been primarily viewed as a nuclear protein, many cells also express variable levels of cytoplasmic TBLR1 and its cytoplasmic specific functions have not been studied. Prostate cancer (PCa) cells express moderately higher level of cytoplasmic TBLR1 compared to benign prostate cells. When comparing androgen-dependent (AD) to androgen-independent (AI) PCa, AI cells contain very high levels of TBLR1 cytoplasmic expression and low levels of nuclear expression. Overexpression of cytoplasmic TBLR1 in AD cells inhibits apoptosis induced by androgen deprivation therapy, either in an androgen free condition or in the presence of bicalutamide. Additionally, we identified a cytoplasmic specific isoform of TBLR1 (cvTBLR1) approximately 5 kDa lower in molecular weight, that is expressed at higher levels in AI PCa cells. By immunoprecipitation, we purified cvTBLR1 and using mass spectrometry analysis combined with N-terminal TMPP labeling and Edman degradation, we identified the cleavage site of cvTBLR1 at amino acid 89, truncating the first 88 amino acids of the N-terminus of the full length protein. Functionally, cvTBLR1 expressed in the cytoplasm reduced apoptosis in PCa cells and promoted growth, migration, and invasion. Finally, we identified a nuclear export signal sequence for TBLR1 cellular localization by deletion and site-directed mutagenesis. The roles of TBLR1 and cvTBLR1 provide novel insights into the mechanism of castration resistance and new strategies for PCa therapy.
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