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Helen Diller Family Comprehensive Cancer Center

Researchers Unlock Secret of Deadly Brain Cancer's "Immortality"

New Therapeutic Target Identified in Glioblastoma Could Be Effective Against a Common Immortality Mechanism in One Third of Human Cancers

By Nicholas Weiler | UCSF.edu | September 10, 2018

Researchers Unlock Secret of Deadly Brain Cancer's

Glioblastoma characterized by "palisading necrosis" (red). Credit: Costello Lab/UCSF.

UC San Francisco researchers have discovered how a mutation in a gene regulator called the TERTpromoter — the third most common mutation among all human cancers and the most common mutation in the deadly brain cancer glioblastoma — confers “immortality” on tumor cells, enabling the unchecked cell division that powers their aggressive growth. 

The research, published September 10, 2018 in Cancer Cell, found that patient-derived glioblastoma cells with TERT promoter mutations depend on a particular form of a protein called GABP for their survival. GABP is critical to the workings of most cells, but the researchers discovered that the specific component of this protein that activates mutated TERT promoters, a subunit called GABP-β1L, appears to be dispensable in normal cells: Eliminating this subunit using CRISPR-based gene editing dramatically slowed the growth of the human cancer cells in lab dishes and when they were transplanted into mice, but removing GABP-β1L from healthy cells had no discernable effect. 

“These findings suggest that the β1L subunit is a promising new drug target for aggressive glioblastoma and potentially the many other cancers with TERT promoter mutations,” said study senior author Joseph Costello, PhD, a leading UCSF neuro-oncology researcher.

Immortality is one of the key traits of cancer cells. In contrast to healthy cells, which are strictly limited in the number of times they are able to divide, cancer cells can go on dividing and multiplying forever, in many cases accumulating additional cancer-driving mutations as they go.

Normally, cellular life spans are set by structures called telomeres — protective caps that sit at the ends of chromosomes like the aglets at the end of a shoelace. Telomeres shorten each time a cell divides, until eventually they are too short to protect the DNA any longer, a signal the cell has reached the end of its natural life span and should be retired like a balding car tire. 

Tumor cells in most cancers get around this limitation by stealing the secret of immortality from long-lived stem cells, which can divide indefinitely thanks to a telomere-extending enzyme called telomerase, the discovery of which led to a Nobel prize shared by UCSF’s Elizabeth Blackburn, PhD. Normally only stem cells are allowed to cheat death in this way, but scientists estimate that as many as 90 percent of human cancers have activated telomerase, many through mutations in TERT, one of the two genes that encodes the telomerase complex, which enable them to grow and spread unfettered by the limitations of normal cells. 

Efforts to treat cancers with drugs that block telomerase have mostly proven too toxic to patients because they interfere with telomere maintenance in stem cells such as those needed to maintain healthy blood.

But recent research has suggested that more than 50 types of human cancers may be caused not by a defective TERT gene itself, but by mutations in the TERT promoter — a region of DNA where protein complexes called transcription factors can influence when and how the TERT gene is activated. These mutations enable a transcription factor called GABP to bind to the TERT promoter and activate it, other studies had found, which was strange because in healthy cells GABP and TERT usually have nothing to do with one another.

“This was really intriguing to us,” Costello said. “You can’t create a drug to target a promoter itself, but if we could identify how GABP was binding to the mutated promoter in these cancers, we might have a remarkably powerful new drug target.” 

Costello’s team, led by graduate students Andrew Mancini and Ana Xavier-Magalhaes, studied human glioblastoma cell lines and primary tumor cells derived from advanced-stage glioblastoma patients and showed that the cells’ mutations create two adjacent sequences of DNA in the TERT promoter that make a perfect landing pad for a particular form of the GABP transcription factor complex containing four subunits, one of which was GABP-β1L. 

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