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J. Biol. Chem., Vol. 282, Issue 36, 26460-26470, September 7, 2007

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Tumor-specific Activation of Human Telomerase Reverses Transcriptase Promoter Activity by Activating Enhancer-binding Protein-2 in Human Lung Cancer Cells^*

From the Section of Thoracic Molecular Oncology, Department of Thoracic and Cardiovascular Surgery, University of Texas M. D. Anderson Cancer Center, Houston, Texas, 77030

The up-regulated expression and telomerase activity of human telomerase reverse transcriptase (hTERT) are hallmarks of tumorigenesis. The hTERT promoter has been shown to promote hTERT gene expression selectively in tumor cells but not in normal cells. However, little is known about how tumor cells differentially activate hTERT transcription and induce telomerase activity. In this study, we identified activating enhancer-binding protein-2 (AP-2) as a novel transcription factor that specifically binds to and activates the hTERT promoter in human lung cancer cells. AP-2 was detected in hTERT promoter DNA-protein complexes formed in nuclear extracts prepared only from lung cancer cells but not from normal cells. We verified the tumor-specific binding activity of AP-2 for the hTERT promoter in vitro and in vivo and detected high expression levels of AP-2 in lung cancer cells. We found that ectopic expression of AP-2 reactivated hTERT promoter-driven reporter green fluorescent protein (GFP) gene and endogenous hTERT gene expression in normal cells, enhanced GFP gene expression in lung cancer cells, and prolonged the life span of primary lung bronchial epithelial cells. Furthermore, we found that inhibition of endogenous AP-2 expression by AP-2 gene-specific small interfering RNAs effectively attenuated hTERT promoter-driven GFP expression, suppressed telomerase activity, accelerated telomere shortening, and inhibited tumor cell growth by induction of apoptosis in lung cancer cells. Our results demonstrate the tumor-specific activation of the hTERT promoter by AP-2 and imply the potential of AP-2 as a novel tumor marker or a cancer therapeutic target.

Received for publication, November 14, 2006 , and in revised form, July 12, 2007.

^* This work was supported by NCI Specialized Program of Research Excellence Grants CA70970, MMHCC U01CA10535201, and R01CA116322 from the National Institutes of Health (to L. J.); Department of Defense TARGET Lung Cancer Programs Grant DAMD17-02-1-070; NCI Support Core Grant CA16672 from the National Institutes of Health (to the M. D. Anderson Cancer Center); and a grant from the Tobacco Settlement Funds as appropriated by the Texas State Legislature. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Dept. of Thoracic and Cardiovascular Surgery, Unit 445, University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030. Tel.: 713-563-9143; Fax: 713-794-4901; E-mail: lji{at}mdanderson.org.

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