Understanding and exploiting hTERT promoter regulation for diagnosis and treatment of human cancers

Satoru Kyo, Masahiro Takakura, Toshiyoshi Fujiwara, Masaki Inoue

Research output: Contribution to journalArticle

226 Citations (Scopus)

Abstract

Telomerase activation is a critical step for human carcinogenesis through the maintenance of telomeres, but the activation mechanism during carcinogenesis remains unclear. Transcriptional regulation of the human telomerase reverse transcriptase (hTERT) gene is the major mechanism for cancer-specific activation of telomerase, and a number of factors have been identified to directly or indirectly regulate the hTERT promoter, including cellular transcriptional activators (c-Myc, Sp1, HIF-1, AP2, ER, Ets, etc.) as well as the repressors, most of which comprise tumor suppressor gene products, such as p53, WT1, and Menin. Nevertheless, none of them can clearly account for the cancer specificity of hTERT expression. The chromatin structure via the DNA methylation or modulation of nucleosome histones has recently been suggested to be important for regulation of the hTERT promoter. DNA unmethylation or histone methylation around the transcription start site of the hTERT promoter triggers the recruitment of histone acetyltransferase (HAT) activity, allowing hTERT transcription. These facts prompted us to apply these regulatory mechanisms to cancer diagnostics and therapeutics. Telomerase-specific replicative adenovirus (Telomelysin, OBP-301), in which E1A and E1B genes are driven by the hTERT promoter, has been developed as an oncolytic virus that replicates specifically in cancer cells and causes cell death via viral toxicity. Direct administration of Telomelysin was proved to effectively eradicate solid tumors in vivo, without apparent adverse effects. Clinical trials using Telomelysin for cancer patients with progressive stages are currently ongoing. Furthermore, we incorporated green fluorescent protein gene (GFP) into Telomelysin (TelomeScan, OBP-401). Administration of TelomeScan into the primary tumor enabled the visualization of cancer cells under the cooled charged-coupled device (CCD) camera, not only in primary tumors but also the metastatic foci. This technology can be applied to intraoperative imaging of metastatic lymphnodes. Thus, we found novel tools for cancer diagnostics and therapeutics by utilizing the hTERT promoter.

Original languageEnglish
Pages (from-to)1528-1538
Number of pages11
JournalCancer Science
Volume99
Issue number8
DOIs
Publication statusPublished - 2008

Fingerprint

Neoplasms
Telomerase
Histones
Carcinogenesis
human TERT protein
Oncolytic Viruses
Genes
Histone Acetyltransferases
Nucleosomes
Transcription Initiation Site
Telomere
DNA Methylation
Green Fluorescent Proteins
Tumor Suppressor Genes
Adenoviridae
Methylation
Reverse Transcription
Chromatin
Cause of Death
Cell Death

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Understanding and exploiting hTERT promoter regulation for diagnosis and treatment of human cancers. / Kyo, Satoru; Takakura, Masahiro; Fujiwara, Toshiyoshi; Inoue, Masaki.

In: Cancer Science, Vol. 99, No. 8, 2008, p. 1528-1538.

Research output: Contribution to journalArticle

Kyo, Satoru ; Takakura, Masahiro ; Fujiwara, Toshiyoshi ; Inoue, Masaki. / Understanding and exploiting hTERT promoter regulation for diagnosis and treatment of human cancers. In: Cancer Science. 2008 ; Vol. 99, No. 8. pp. 1528-1538.
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