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.
Highlights
Inactivation of tumor suppressor genes due to gene alterations, notably loss of heterozygosity (LOH), plays a major role in the development of common human adult cancers [1, 2], with breast cancer as a good example [38]
We have shown that reduced PinX1 expression activates telomerase and leads to telomere lengthening and chromosome instability, which can be fully rescued by TERT knockdown or knockout [82], confirming that PinX1 acts as a telomerase inhibitor to regulate telomere maintenance
Given activation of telomerase in most human cancers and common downregulation of PinX1 in liver, gastric and breast cancers [13, 26, 82], these results indicate that PinX1 is a major tumor suppressor, whose downregulation activates telomerase, induces chromosome instability and eventually leads to tumorigenesis by [82]
Summary
Identified as a TRF1/Pin2-binding protein, PinX1 is a potent telomerase inhibitor. Emerging evidence suggest that PinX1 and especially its small telomerase inhibitory domain might be a potential new drug target for treat cancers that have telomerase activation. Many questions remained to be addressed including how PinX1 regulates chromosome stability and tumorigenesis, how PinX1 is regulated under physiological and pathological conditions, how to develop PinX1-based cancer therapy, and whether PinX1 has other new functions. Further studies on this relatively unknown protein would uncover novel insight into the regulation of chromosome stability and tumorigenesis and might eventually lead to new therapies for cancers
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
