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.