Hypoxia-Inducible Factor 1 Mediates Upregulation of Telomerase (hTERT)

Abstract

Hypoxia occurs during the development of the placenta in the first trimester and correlates with both trophoblast differentiation and the induction of telomerase activity through hTERT expression. We sought to determine the mechanism of regulation of hTERT expression during hypoxia. We show that hypoxia-inducible factor 1␣ (HIF-1␣) and hTERT expression in the human placenta decrease with gestational age and that these are overexpressed in preeclamptic placenta, a major complication of pregnancy. Hypoxia not only transactivates the hTERT promoter activity but also enhances endogenous hTERT expression. The hTERT promoter region between ؊165 and ؉51 contains two HIF-1 consensus motifs, and in vitro reporter assays show that these are essential for hTERT transactivation by HIF-1. Introduction of an antisense oligonucleotide for HIF-1 diminishes hTERT expression during hypoxia, indicating that upregulation of hTERT by hypoxia is directly mediated through HIF-1. Our results provide persuasive evidence that the regulation of hTERT promoter activity by HIF-1 represents a mechanism for trophoblast growth during hypoxia and suggests that this may be a generalized response to hypoxia in various human disorders including resistance to cancer therapeutics by upregulating telomerase.

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

“…(a) Koshiji et al observed that hypoxia-induced HIF-1a significantly inhibited hTERT expression in human colon cancer cells, in sharp contrast to other reports (11). (b) Different mechanisms, including transcriptional and post-transcriptional approaches, have been implicated in hypoxia-regulated hTERT expression (10,(12)(13)(14)16). It remains to be defined whether these regulatory pathways contribute to the enhanced hTERT expression or telomerase activity in all human cancer cells.…”

“…In addition to their effect at transcriptional levels, hypoxia or HIF-1a is capable of enhancing telomerase activity via other pathways (10)(11)(12)(13)(14). Alternatively spliced hTERT mRNA contributes to telomerase regulation under certain settings, and it has been established that the full-length hTERT transcripts, rather than any other variants, is translated into a functional protein required for active telomerase (5,6,(24)(25)(26)(27)(28)(29)(30).…”

“…By promoting angiogenesis, HIF-1 plays important roles in progression, invasiveness, or metastasis of malignant diseases (7,8). Furthermore, recent studies have suggested that hypoxic treatment or overexpression of HIF-1a affects hTERT and telomerase expression (10)(11)(12)(13)(14)(15)(16). Most observations showed that the incubation of human cancer cells at lower levels of oxygen enhanced hTERT mRNA expression and telomerase activity via HIF-1a -mediated trans-activation of the hTERT gene.…”

“…The hTERT gene has previously been identified as a direct target of HIF-1a (13,16). We therefore sought to further determine the effect of both HIF-1a and HIF-2a on the hTERT promoter activity in RCC cells.…”

“…We therefore sought to further determine the effect of both HIF-1a and HIF-2a on the hTERT promoter activity in RCC cells. It is known that p181, a reporter construct with an insert of the core hTERT promoter sequence, carries the hypoxia-responsible element (HRE), and that HIF-1a activates the hTERT transcription by binding this HRE (13,16). When p181 was cotransfected with either HIF1a or HIF-2a expression plasmids into A498 and Caki-2 cells, we observed substantial increases in luciferase activity driven by the hTERT core promoter in a dose-dependent manner Hypoxia-induced HIF-1a and/or HIF-2a expression and accompanied changes in hTERT mRNA and its variants in RCC (Caki-2, TK-10 , and A498 ) and glioma (U563, U373 , and U251 ) cell lines.…”