Abstract

Telomerase reactivation is one of the key events in the development of cancer. More than 90% of all cancers de-repress sequences within the genome, which results in the overexpression of hTERT and telomerase. In doing so, telomeres at the ends of human chromosomes, which would naturally shorten after each round of replication, are maintained indefinitely giving rise to immortalized cells. The actual mechanisms responsible for telomerase depression in cancer are still under intense investigation and the elucidation of this process would represent a major therapeutic target. The literature has pointed to genes on different chromosomes being responsible for telomerase repression in specific cancers. Microcell Mediated Chromosome Transfer (MMCT) was used to transfer human chromosomes 3, 8, 10, 11, 13, and 17 into the prostate cancer cell line PC3. In doing so, we observed robust and sustained hTERT and telomerase repression for chromosome 11. We then fragmented chromosome 11 using 25G of gamma radiation before repeating the transfer into PC3. We found that 70% of the hybrid clones picked expressed very low levels of hTERT and telomerase when compared to the controls. STS mapping of the clones identified 3 distinct regions on chromosome 11q which could harbour sequences responsible for telomerase repression specific to prostate cancer. Identification of this telomerase repressor could lead to new chemotherapeutic drugs to target prostate cancer or a highly specific biomarker for the disease.

Keywords:Prostate cancer; Telomerase; hTERT; MMCT; Chromosome 11; Mapping