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Homeodomain protein DLX4 counteracts key transcriptional control mechanisms of the TGF-β cytostatic program and blocks the antiproliferative effect of TGF-β

Oncogene volume 30, pages 2718–2729 (2011)Cite this article

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Abstract

The antiproliferative activity of transforming growth factor-β (TGF-β) is essential for maintaining normal tissue homeostasis and is lost in many types of tumors. Gene responses that are central to the TGF-β cytostatic program include activation of the cyclin-dependent kinase inhibitors, p15Ink4B and p21WAF1/Cip1, and repression of c-myc. These gene responses are tightly regulated by a repertoire of transcription factors that include Smad proteins and Sp1. The DLX4 homeobox patterning gene encodes a transcription factor that is absent from most normal adult tissues, but is expressed in a wide variety of malignancies, including lung, breast, prostate and ovarian cancers. In this study, we demonstrate that DLX4 blocks the antiproliferative effect of TGF-β. DLX4 inhibited TGF-β-mediated induction of p15Ink4B and p21WAF1/Cip1 expression. DLX4 bound and prevented Smad4 from forming complexes with Smad2 and Smad3, but not with Sp1. However, DLX4 also bound and inhibited DNA-binding activity of Sp1. In addition, DLX4 induced expression of c-myc independently of TGF-β/Smad signaling. The ability of DLX4 to counteract key transcriptional control mechanisms of the TGF-β cytostatic program could explain, in part, the resistance of tumors to the antiproliferative effect of TGF-β.

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Abbreviations

Ab:

antibody

BMP:

bone morphogenetic protein

DBD:

DNA-binding domain

EMT:

epithelial-to-mesenchymal transition

F-Luc:

firefly luciferase

IP:

immunoprecipitation

R-Luc:

Renilla luciferase

R-Smad:

receptor-regulated Smad

TGF-β:

transforming growth factor-β

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Acknowledgements

This work was supported by a Schissler Foundation Fellowship (B Trinh), the Vietnam Education Foundation (B Trinh), the US Department of Defense grant W81XWH-06-1-0259 (H Naora) and the National Institutes of Health grant R01 CA141078 (H Naora). We thank Sabine Thonard for technical assistance, and Song Yi Ko, Gary Gallick, Michelle Barton, Janet Price, Peng Huang and Miles Wilkinson (MD Anderson Cancer Center) for helpful discussions.

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  1. Department of Systems Biology, University of Texas MD Anderson Cancer Center, Houston, TX, USA

    B Q Trinh, N Barengo & H Naora

  2. Cancer Biology Program, Graduate School of Biomedical Sciences, University of Texas Health Sciences Center, Houston, TX, USA

    B Q Trinh & H Naora

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Correspondence to H Naora.

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Dr Naora's work has been funded by the NIH and US Department of Defense. The remaining authors declare no conflict of interest.

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Trinh, B., Barengo, N. & Naora, H. Homeodomain protein DLX4 counteracts key transcriptional control mechanisms of the TGF-β cytostatic program and blocks the antiproliferative effect of TGF-β. Oncogene 30, 2718–2729 (2011). https://doi.org/10.1038/onc.2011.4

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