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DNA Damage and Cellular Stress Responses

The Opposing Effect of Hypoxia-Inducible Factor-2 on Expression of Telomerase Reverse Transcriptase

¹ Aging and Health Center, School of Nursing, ² Institute of Urology, The Second Hospital, and ³ Department of Urology, Qilu Hospital, Shandong University, and ⁴ College of Basic Medical Sciences, Shandong University of Traditional Chinese Medicine, Jinan, P.R. China; and ⁵ Department of Medicine, Division of Hematology, Karolinska University Hospital Solna and Karolinska Institutet, Stockholm, Sweden

Requests for reprints: Dawei Xu, Hematology Lab, CMM, L8:03, Karolinska University Hospital, SE-171 76, Stockholm, Sweden. Phone: 46-8-5177-6552; Fax: 46-8-5177-3054. E-mail: Dawei.Xu{at}ki.se

Hypoxia-inducible factor-1 (HIF-1) has been implicated in the transcriptional regulation of the telomerase reverse transcriptase (hTERT) gene expression and telomerase activity, essential elements for cellular immortalization and transformation. However, controversial results were obtained in different studies. Moreover, it is totally unclear whether HIF-2, the paralog of HIF-1, plays a role in regulating hTERT expression. In the present study, we found that hypoxic treatment enhanced hTERT mRNA expression and telomerase activity in three renal cell carcinoma (RCC) cell lines with different genetic backgrounds. Both HIF-1 and HIF-2 were capable of significantly increasing the hTERT promoter activity in these cells. Moreover, depleting HIF-2 led to a down-regulation of hTERT mRNA level in RCC A498 cells expressing constitutive HIF-2. It was found that HIF-2 bound to the hTERT proximal promoter and enhanced the recruitment of the histone acetyltransferase p300 and histone H3 acetylation locally in A498 cells treated with hypoxia. Increased levels of hTERT mRNA were observed in two of three hypoxia-treated malignant glioma cell lines. However, HIF-1 stimulated whereas HIF-2 inhibited the hTERT promoter activity in these glioma cell lines. Ectopic expression of HIF-2 resulted in diminished hTERT expression in glioma cells. Collectively, HIF-1 activates hTERT and telomerase expression in both RCC and glioma cells, and HIF-2 enhances hTERT expression in RCC cells, whereas it represses the hTERT transcription in glioma cells. These findings reveal a complex relationship between HIF-1/2 and hTERT/telomerase expression in malignant cells, which may have both biological and clinical implications. (Mol Cancer Res 2007;5(8):793–800)