PinX1: A Sought-After Major Tumor Suppressor at Human Chromosome 8p23

Abstract

Human chromosome 8p23 is a region that has the most frequent heterozygosity in common human adult epithelial malignancies, but its major tumor suppressor gene(s) remain to be identified. Telomerase is activated in most human cancers and is critical for cancer cell growth. However, little is known about the significance of telomerase activation in chromosome instability and cancer initiation. The gene encoding the potent and highly conserved endogenous telomerase inhibitor PinX1 is located at human chromosome 8p23. However, the role of PinX1 in telomerase regulation and cancer development is not clear. Recent works from our group indicate that PinX1 is critical for maintaining telomere length at the optimal length. Furthermore, PinX1 is reduced in a large subset of human breast cancer tissues and cells. Significantly, PinX1 inhibition activates telomerase, and elongates telomeres, eventually leading to chromosome instability, all of which are abrogated by telomerase knockdown or knockout. Moreover, PinX1 allele loss causes majority of mice to develop a variety of epithelial cancers, which display chromosome instability and recapitulate to 8p23 allele loss in humans. These results indicate that PinX1 is a sought-after major tumor suppressor at human chromosome 8p23 that is essential for regulating telomerase activity and maintaining chromosome stability. These results suggest that inhibition of telomerase using PinX1 especially its telomerase inhibitory fragment or other methods might be used to treat cancers that have telomerase activation.