TBLR1 as an androgen receptor (AR) coactivator selectively activates AR target genes to inhibit prostate cancer growth

Daniels, Garrett; Li, Yirong; Gellert, Lan L.; Zhou, Albert E.; Melamed, Jonathan; Wu, Xinyu; Zhang, Xinmin; Zhang, David Y.; Meruelo, Daniel; Logan, Susan K.; Basch, Ross S.; Lee, Peng

doi:10.1530/erc-13-0293

Cited by 28 publications

(36 citation statements)

References 32 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Moreover, the functions of TBL1XR1 were distinct in different tumors. In prostate cancer, TBL1XR1 was reported to function as a tumor suppressor and inhibit tumor growth, perhaps through regulating androgen receptor (AR) signaling pathway (Daniels et al 2014. However, TBL1XR1 has been reported to be highly expressed in cervical cancer , breast cancer , nasopharyngeal carcinoma , hepatocellular carcinoma (Kuang et al 2016), digestive cancers (Liu et al 2016a;Zhou et al 2016;Liu et al 2017), and ovarian cancer .…”

Section: Introductionmentioning

confidence: 99%

Over-Expression of TBL1XR1 Indicates Poor Prognosis of Serous Epithelial Ovarian Cancer

2017

Tohoku J. Exp. Med.

View full text Add to dashboard Cite

Transducin (β)-like 1 X-linked receptor 1 (TBL1XR1) is a core component of the NCoR/SMRT transcription co-repressor complex, and its role in regulating cancer progression has been reported. Serous epithelial ovarian cancer (EOC) is the most common histological type of EOC. Here we explored the significance of TBL1XR1 expression in predicting outcomes of patients with serous EOC. Real-time quantitative PCR analysis showed that the expression level of TBL1XR1 mRNA was significantly higher in EOC tissues compared with adjacent non-tumorous tissues. The protein levels of TBL1XR1 in EOC tissues were assessed by immunohistochemistry, and the patients were classified into low-expression group (n = 62) and high-expression group (n = 54) according to the immunoreactivity. Prognostic significance of TBL1XR1 was evaluated by univariate and multivariate analyses, showing that over-expression of TBL1XR1 was correlated with poor prognosis. In addition, TBL1XR1 was positively associated with the lymph node metastasis of EOC. Because vascular endothelial growth factor (VEGF)-C is known as a critical mediator of lymph node metastasis, we measured the expression level of VEGF-C mRNA in EOC tissues and thus identified a positive correlation between TBL1XR1 and VEGF-C mRNA levels. Subsequently, using human EOC cell lines, we showed that silencing of TBL1XR1 decreased VEGF-C expression, suggesting that TBL1XR1 may function as an upstream regulator of VEGF-C in EOC. Furthermore, the proliferation and invasion of EOC cells were inhibited by TBL1XR1 silencing. In conclusion, TBL1XR1 overexpression may be an unfavorable prognostic factor for EOC. We also suggest that the TBL1XR1-VEGF-C axis may determine the EOC progression.

show abstract

Section: Introductionmentioning

confidence: 99%

Over-Expression of TBL1XR1 Indicates Poor Prognosis of Serous Epithelial Ovarian Cancer

2017

Tohoku J. Exp. Med.

View full text Add to dashboard Cite

show abstract

“…Previously our lab showed that TBLR1 was expressed as both nuclear and cytoplasmic protein [15]. In PCa cells, nuclear expression of TBLR1 was significantly reduced in comparison to benign prostate cells.…”

Section: Resultsmentioning

confidence: 99%

“…Previously our lab showed that overexpression of nuclear TBLR1 in AD LNCaP cells inhibited growth in an androgen-dependent manner by cell cycle arrest but this overexpression had no effect on apoptosis [15]. To test the function of cytoplasmic TBLR1, we created stable LNCaP cell lines overexpressing TBLR1 in the cytoplasm utilizing a fusion construct of the nuclear export sequence (NES) (MLQKKLEELE) to the N-terminus of TBLR1.…”

Section: Resultsmentioning

confidence: 99%

“…Our previous study has shown that TBLR1 is a transcriptional activator of AR and its nuclear expression is significantly reduced in PCa compared with benign prostate glands. Forced expression of nuclear TBLR1 leads to androgen-dependent growth suppression of prostate cancer cells in vitro and in vivo by selective activation of androgen-regulated genes associated with differentiation and growth suppression [15]. In addition to its nuclear localization, TBLR1 can also be a cytoplasmic protein.…”

Section: Discussionmentioning

confidence: 99%

“…TBLR1 is a ubiquitously expressed protein [14]. Immunohistochemical data shows TBLR1 as primarily a nuclear protein in normal prostate but shows reduced nuclear expression in PCa [15]. TBLR1 is also a strong coactivator of AR in prostate cancer, leading to selective activation of growth suppressive AR target genes and tumor suppression.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Cytoplasmic, full length and novel cleaved variant, TBLR1 reduces apoptosis in prostate cancer under androgen deprivation

et al. 2016

Self Cite

View full text Add to dashboard Cite

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.

show abstract

Androgen Receptor Coactivators in Regulation of Growth and Differentiation in Prostate Cancer

Čulig

2015

Journal Cellular Physiology

View full text Add to dashboard Cite

Androgen receptor (AR) is a key factor in regulation of growth and differentiation in normal and malignant prostate. Endocrine therapies for prostate cancer include inhibition of androgen production either by analogs of luteinizing hormone releasing hormone or abiraterone acetate and/or use of anti-androgens such as hydroxyflutamide, bicalutamide, and enzalutamide. Castration therapy-resistant cancer develops inevitably in patients who undergo treatment. AR coactivators are proteins which interact with one or more regions of the AR thus enhancing its function. Although several functions of AR coactivators may be redundant, specific functions have been identified and analyzed. The p160 group of coactivators, SRC-1, -2, and -3 not only potentiate the activation of the AR, but are also implicated in potentiation of function of insulin-like growth factor-I and activation of the Akt pathway. Transcriptional integrators p300 and CBP are up-regulated by androgen ablation and may influence antagonist/agonist balance of non-steroidal anti-androgens. A therapy approach designed to target p300 in prostate cancer revealed its role in regulation of proliferation of migration of androgen-sensitive and -insensitive prostate cancer cells. Coactivators p300 and SRC-1 are required for AR activation by interleukin-6 (IL-6), a cytokine that is overexpressed in castration therapy-resistant prostate cancer. Some coactivators, such as Vav3, are involved in regulation of transcriptional activity of truncated AR, which emerge during endocrine thrapy. Stimulation of cellular migration and invasion by AR coactivators has also been described. Translational studies with aim to introduce anti-AR coactivator therapy have not been successfully implemented in the clinic so far.

show abstract

TBLR1 as an androgen receptor (AR) coactivator selectively activates AR target genes to inhibit prostate cancer growth

Cited by 28 publications

References 32 publications

Over-Expression of TBL1XR1 Indicates Poor Prognosis of Serous Epithelial Ovarian Cancer

Over-Expression of TBL1XR1 Indicates Poor Prognosis of Serous Epithelial Ovarian Cancer

Cytoplasmic, full length and novel cleaved variant, TBLR1 reduces apoptosis in prostate cancer under androgen deprivation

Androgen Receptor Coactivators in Regulation of Growth and Differentiation in Prostate Cancer

Contact Info

Product

Resources

About