The opposing effect of hypoxia-inducible factor-2alpha on expression of telomerase reverse transcriptase.
Hypoxia-inducible factor-1alpha (HIF-1alpha) 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-2alpha, the paralog of HIF-1alpha, 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-1alpha and HIF-2alpha were capable of significantly increasing the hTERT promoter activity in these cells. Moreover, depleting HIF-2alpha led to a down-regulation of hTERT mRNA level in RCC A498 cells expressing constitutive HIF-2alpha. It was found that HIF-2alpha 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-1alpha stimulated whereas HIF-2alpha inhibited the hTERT promoter activity in these glioma cell lines. Ectopic expression of HIF-2alpha resulted in diminished hTERT expression in glioma cells. Collectively, HIF-1alpha activates hTERT and telomerase expression in both RCC and glioma cells, and HIF-2alpha enhances hTERT expression in RCC cells, whereas it represses the hTERT transcription in glioma cells. These findings reveal a complex relationship between HIF-1alpha/2alpha and hTERT/telomerase expression in malignant cells, which may have both biological and clinical implications.
Lou
Fenglan
F
Aging and Health Center, School of Nursing, Institute of Urology, The Second Hospital, and Department of Urology, Shandong University, College of Basic Medical Sciences, Jinan, China.
Chen
Xinxia
X
Jalink
Marit
M
Zhu
Qingjun
Q
Ge
Nan
N
Zhao
Shengtian
S
Fang
Xiaolei
X
Fan
Yidong
Y
Björkholm
Magnus
M
Liu
Zhaoxu
Z
Xu
Dawei
D
D000107:Acetylation; D051792:Basic Helix-Loop-Helix Proteins / Q000502:physiology*; D015153:Blotting, Western; D002292:Carcinoma, Renal Cell / Q000235:genetics* / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000378:metabolism; D047369:Chromatin Immunoprecipitation; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology*; D005910:Glioma / Q000235:genetics* / Q000378:metabolism; D051548:Histone Acetyltransferases / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D006801:Humans; D000860:Hypoxia; D007680:Kidney Neoplasms / Q000235:genetics / Q000378:metabolism; D008156:Luciferases / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019098:Telomerase / Q000235:genetics* / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor; D000099162:Endothelial PAS Domain-Containing Protein 1
D051792:Basic Helix-Loop-Helix Proteins; D018797:Cell Cycle Proteins; D051548:Histone Acetyltransferases; D006657:Histones; D008156:Luciferases; D012333:RNA, Messenger; D019098:Telomerase; D014157:Transcription Factors; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor; D000099162:Endothelial PAS Domain-Containing Protein 1; C509186:TERT protein, human