Transcriptional regulation of the telomerase hTERT gene as a target for cellular and viral oncogenic mechanisms

• Published in: Carcinogenesis (New York) Vol. 24; no. 7; pp. 1167 - 1176
• Main Authors: Horikawa, Izumi, Barrett, J. Carl
• Format: Journal Article
• Language: English
• Published: Oxford Oxford University Press 01-07-2003; Oxford Publishing Limited (England)
• Subjects: 5-aza-2′-deoxycytidine; 5-aza-C; AE6 protein; Biological and medical sciences; Cell physiology; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes; Cell Transformation, Viral - physiology; chromosome 3; DNA Methylation; DNA-Binding Proteins; E6 protein; electrophoretic mobility shift assay; EMSA; Fundamental and applied biological sciences. Psychology; Gene Expression Regulation, Enzymologic - physiology; HAT; HBV; HDAC; Hepatitis B virus; histone acetyltransferase; histone deacetylase; HPV; hTERT; hTERT gene; Human papillomavirus; human telomerase reverse transcriptase; Humans; microcell-mediated chromosome transfer; MMCT; Molecular and cellular biology; Papillomaviridae - physiology; Telomerase - genetics; Telomere - metabolism; TERT gene; Transcription, Genetic; Transcriptional Activation; Catalytic subunit; Signal transduction; Nucleotidyltransferases; Transcription; Enzyme; Transferases; Malignant transformation; Onc gene; Mechanism of action; Cell transformation; Carcinogenesis; Telomerase
• ISSN: 0143-3334; 1460-2180
• DOI: 10.1093/carcin/bgg085

Malignant transformation from mortal, normal cells to immortal, cancer cells is generally associated with activation of telomerase and subsequent telomere maintenance. A major mechanism to regulate telomerase activity in human cells is transcriptional control of the telomerase catalytic subunit gene, human telomerase reverse transcriptase (hTERT). Several transcription factors, including oncogene products (e.g. c-Myc) and tumor suppressor gene products (e.g. WT1 and p53), are able to control hTERT transcription when over-expressed, although it remains to be determined whether a cancer-associated alteration of these factors is primarily responsible for the hTERT activation during carcinogenic processes. Microcell-mediated chromosome transfer experiments have provided evidence for endogenous factors that function to repress the telomerase activity in normal cells and are inactivated in cancer cells. At least one of those endogenous telomerase repressors, which is encoded by a putative tumor suppressor gene on chromosome 3p, acts through transcriptional repression of the hTERT gene. The hTERT gene is also a target site for viruses frequently associated with human cancers, such as human papillomavirus (HPV) and hepatitis B virus (HBV). HPV E6 protein contributes to keratinocyte immortalization and carcinogenesis through trans-activation of the hTERT gene transcription. In at least some hepatocellular carcinomas, the hTERT gene is a non-random integration site of HBV genome, which activates in cis the hTERT transcription. Thus, a variety of cellular and viral oncogenic mechanisms converge on transcriptional control of the hTERT gene. Regulation of chromatin structure through the modification of nucleosomal histones may mediate the action of these cellular and viral mechanisms. Further elucidation of the hTERT transcriptional regulation, including identification and characterization of the endogenous repressor proteins, should lead to better understanding of the complex regulation of human telomerase in normal and cancer cells and may open up new strategies for anticancer therapy.