TWIST1, A novel androgen-regulated gene, is a target for NKX3-1 in prostate cancer cells

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Abstract

Background

TWIST1 plays a key role in EMT-mediated tumor invasion and metastasis. Since bone metastasis is a hallmark of advanced prostate cancer and is detected in at least 85% of patients who die of this disease, it is of great importance to understand the regulation of the cellular signaling pathways involved in the metastatic process.

Methods

Prostatic cell lines were analyzed using real time RT-PCR, chromatin immunoprecipitations (ChIP) and transfection of siRNA’s and reporter constructs.

Results

We report in this paper that TWIST1 is an androgen-regulated gene under tight regulation of NKX3-1. Androgens repress the expression of TWIST1 via NKX3-1, which is a prostate–specific tumor suppressor that is down-regulated in the majority of metastatic prostate tumors. We show that NKX3-1 binds to the TWIST1 promoter and that NKX3-1 over-expression reduces the activity of a TWIST1 promoter reporter construct, whereas NKX3-1 siRNA up-regulates endogenous TWIST1 mRNA in prostate cancer cells.

Conclusion

Our finding that NKX3-1 represses TWIST1 expression emphasizes the functional importance of NKX3-1 in regulating TWIST1 expression during prostate cancer progression to metastatic disease.

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Most cited references 19

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MatInd and MatInspector: new fast and versatile tools for detection of consensus matches in nucleotide sequence data.

Kerstin Quandt, Kornelie Frech, Holger Karas … (1995)

The identification of potential regulatory motifs in new sequence data is increasingly important for experimental design. Those motifs are commonly located by matches to IUPAC strings derived from consensus sequences. Although this method is simple and widely used, a major drawback of IUPAC strings is that they necessarily remove much of the information originally present in the set of sequences. Nucleotide distribution matrices retain most of the information and are thus better suited to evaluate new potential sites. However, sufficiently large libraries of pre-compiled matrices are a prerequisite for practical application of any matrix-based approach and are just beginning to emerge. Here we present a set of tools for molecular biologists that allows generation of new matrices and detection of potential sequence matches by automatic searches with a library of pre-compiled matrices. We also supply a large library (> 200) of transcription factor binding site matrices that has been compiled on the basis of published matrices as well as entries from the TRANSFAC database, with emphasis on sequences with experimentally verified binding capacity. Our search method includes position weighting of the matrices based on the information content of individual positions and calculates a relative matrix similarity. We show several examples suggesting that this matrix similarity is useful in estimating the functional potential of matrix matches and thus provides a valuable basis for designing appropriate experiments.

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Cadherin expression in carcinomas: role in the formation of cell junctions and the prevention of invasiveness.

W Birchmeier, Timothy E. J. Behrens (1994)

It has been realized that the loss of epithelial differentiation in carcinomas, which is accompanied by higher mobility and invasiveness of the tumor cells, is often a consequence of reduced intercellular adhesion. A variety of recent reports have indicated that the primary cause for the 'scattering' of the cells in invasive carcinomas is a disturbance of the integrity of intercellular junctions, often involving loss of a functional cell-cell adhesion molecule E-cadherin. It has also been suggested that during invasion, carcinoma cells convert to a sort of mesenchymal stage, as do normal epithelial cells during development. In the present review, permanent and transient molecular mechanisms are discussed which lead to the impairment of junction integrity of the epithelial cells and thus to the progression of carcinomas towards a more metastatic state. Furthermore, the now extensive literature on the down-regulation of E-cadherin expression in human and animal carcinomas is reviewed in detail.

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Activation of β-catenin and Akt pathways by Twist are critical for the maintenance of EMT associated cancer stem cell-like characters

Junlin Li, Binhua Zhou (2011)

Background Epithelial-mesenchymal transition (EMT) not only confers tumor cells with a distinct advantage for metastatic dissemination, but also it provides those cells with cancer stem cell-like characters for proliferation and drug resistance. However, the molecular mechanism for maintenance of these stem cell-like traits remains unclear. Methods In this study, we induced EMT in breast cancer MCF7 and cervical cancer Hela cells with expression of Twist, a key transcriptional factor of EMT. The morphological changes associated with EMT were analyzed by immunofluorescent staining and Western blotting. The stem cell-like traits associated with EMT were determined by tumorsphere-formation and expression of ALDH1 and CD44 in these cells. The activation of β-catenin and Akt pathways was examined by Western blotting and luciferase assays. Results We found that expression of Twist induced a morphological change associated with EMT. We also found that the cancer stem cell-like traits, such as tumorsphere formation, expression of ALDH1 and CD44, were significantly elevated in Twist-overexpressing cells. Interestingly, we showed that β-catenin and Akt pathways were activated in these Twist-overexpressing cells. Activation of β-catenin correlated with the expression of CD44. Knockdown of β-catenin expression and inhibition of the Akt pathway greatly suppressed the expression of CD44. Conclusions Our results indicate that activation of β-catenin and Akt pathways are required for the sustention of EMT-associated stem cell-like traits.

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Author and article information

Journal

Journal ID (nlm-ta): Cancer Cell Int

Journal ID (iso-abbrev): Cancer Cell Int

Title: Cancer Cell International

Publisher: BioMed Central

ISSN (Electronic): 1475-2867

Publication date Collection: 2013

Publication date (Electronic): 31 January 2013

Volume: 13

Page: 4

Affiliations

[1 ]Department of Tumor Biology, Institute for Cancer Research, Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway

[2 ]Faculty of Medicine, University of Oslo, Oslo, Norway

[3 ]Division of Molecular Medicine, Beckman Research Institute of the City of Hope, Duarte, 91010-3011, CA, USA

[4 ]Department of Urology, Mayo Clinic and Foundation, Rochester, 55905, MN, USA

Article

Publisher ID: 1475-2867-13-4

DOI: 10.1186/1475-2867-13-4

PMC ID: 3626792

PubMed ID: 23368843

SO-VID: 5582c5eb-309e-4ce5-9307-5460dacec9f0

License:

This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

TWIST1, A novel androgen-regulated gene, is a target for NKX3-1 in prostate cancer cells

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Abstract

Background

Methods

Results

Conclusion

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Universal stem cells

Most cited references 19

MatInd and MatInspector: new fast and versatile tools for detection of consensus matches in nucleotide sequence data.

Cadherin expression in carcinomas: role in the formation of cell junctions and the prevention of invasiveness.

Activation of β-catenin and Akt pathways by Twist are critical for the maintenance of EMT associated cancer stem cell-like characters

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