Telomerase inhibitor PINX1 is a key tumor suppressor

Telomeres are ends of choromosomes. For cell division to start and complete ends of chromosomes are essential. Without these, cell can’t divide any more. Each cell can divide a finite number of times before it’s done. It acts like a timer. When the time is up, the cells stop dividing and we die. This is a natural process. The number of ticks that a cell has is called the Hayflick limit.
If by any means the telomeres are repaired, the cell can live beyond the Hayflick limit. If the telomeres are continuously rebuilt then the cell becomes immortal. While that’s exciting, this is exactly what a cancer cell is – immortal. It becomes immortal at the cost of the rest of the healthy cells in the body and deprive them of resources.
There is an enzyme called Telomerase that essentially has the ability to rebuild the ends of choromosomes – telomeres. Embryonic stem cells express telomerase, which allows them to divide repeatedly and form the individual. In adults, telomerase is highly expressed in cells that need to divide regularly (e.g., in the immune system), whereas most somatic cells express it only at very low levels in a cell-cycle-dependent manner.
Beth Israel Deaconess Medical Center (BIDMC) scientists Kun Ping Lu, MD, PhD and Xiao Zhen Zhou, MD, discovered PinX1, the first potent endogenous protein shown to inhibit telomerase in mammals.

The same team has now discovered a vitally important new function for this telomerase inhibitor. The investigators report in the Journal of Clinical Investigation (JCI) that low levels of PinX1 contribute to cancer development, providing the first genetic evidence linking telomerase activation to chromosome instability and cancer initiation, and suggesting a new avenue of treatment for cancers.

"Although telomerase is activated in 85 to 90 percent of human cancers, little has been known about the significance of telomerase activation in chromosome instability and cancer initiation," explains Lu, the paper’s senior author and a Professor of Medicine at Harvard Medical School. "We have discovered, for the first time, a novel role for abnormal telomerase activation in cancer initiation. This suggests that telomerase inhibition using PinX1 or other small molecules may be used to treat certain cancers with activated telomerase."

"A normal cell has 46 chromosomes," Lu explains. "The consequence of chromosomal instability is an imbalance in this number, which allows a cell to evade its normal regulatory mechanism and become a cancer cell. The gene encoding the telomerase inhibitor PinX1 is located at human chromosome 8p23, one of the most frequent regions showing genetic changes in common human malignancies. We, therefore, wanted to find out if PinX1 might have a hand in this."

To address this question, the scientists first looked at PinX1 expression in human breast cancer tissue and cells.

"We found that PinX1 expression was much lower than normal in these cells," explains Zhou, an Assistant Professor of Medicine at HMS and the paper’s first author. "Only 10 percent of the tissue expressed PinX1 levels even close to normal, with the remaining 90 percent expressed much lower than PinX1."

To determine the consequence of this significant PinX1 reduction, the researchers next created cells and mouse models in which the PinX1 gene was partially or completely removed. They observed that while mice or cells completely lacking PinX1 could not survive, the deletion of just one copy of the PinX1 gene actually reduced PinX1 expression — and activated telomerase activity in both mice and cells.

"Surprisingly, we found that the reduced PinX1 in cells not only caused telomerase activation, but also triggered chromosome instability, a phenotype that was fully prevented by inhibiting telomerase," explains Zhou. "More important, most of the PinX1 mutant mice spontaneously developed carcinomas." These mouse tumors, she adds, exhibited features commonly seen in advanced human carcinomas, including distant metastasis and shared tissues of origin with human cancer types linked to 8p23 alterations.

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