Jun 17, 2019 | Updated: 11:38 AM EDT

Potential New Cancer Therapeutic Strategies Involving Inhibition of UNC45A

Apr 19, 2019 09:38 AM EDT

Potential New Cancer Therapeutic Strategies Involving Inhibition of UNC45A
(Photo : Phil Jones, Senior Photographer, Augusta University)

The very first step toward the development of targeted cancer therapy is to identify a protein that plays a significant role in cancer cell growth. It is predominantly promising when this protein is dispensable for the growth of healthy cells.

The Georgia Cancer Center at Augusta University researchers led by Dr. Ahmed Chadli has discovered that UNC45A fits these criteria and they are excited about the potential new cancer therapeutic strategies that involve inhibition of UNC45A.

Scientists have long recognized UNC45A as a molecular chaperone responsible for helping other proteins reach their functional state by guiding protein folding. Though it has a distinct role in cancer, it has its over-expression in the breast, and ovarian cancer patient tissue correlates with grade and stage of the disease. When they have confirmed that UNC45A is not required for the proliferation of healthy breast cells, the team of Dr. Chadli showed that in both cell and mouse models of breast cancer, UNC45A is necessary for cancer cell proliferation and tumor growth.

When they published the underlying molecular mechanism in the Journal of Biological Chemistry, the researchers demonstrated that when they silenced UNC45A expression, an enzyme called NEK7 was also down-regulated by 2-fold. NEK7 plays a vital role in cell proliferation by orchestrating the proper separation of chromosomes during cell division. By silencing UNC45A or deleting NEK7, they had the result of decreased cancer cell proliferation, and adding NEK7 to UNC45A-silenced cells restored proliferation capacity.

The researchers also studied normal against cancer cells lines and normal against cancerous human breast tissues; their observation was significantly more UNC45A present inside (versus outside) of a cell's nucleus. Furthermore, in their study, they found out that in the nucleus, UNC45A interacts with a protein called the glucocorticoid receptor that, in return, promotes NEK7 expression.

The researchers further explored the effect of silenced UNC45A on cell replication because of NEK7's crucial role in cell division. Essentially, they discovered that silencing UNC45A, which has the result of NEK7 down-regulation, caused the cancer cells to undergo what is known as mitotic catastrophe and die, exemplifying the ultimate therapeutic goal.

They captured this result in a dramatic set of real-time videos of cell division in normal versus UNC45-deficient cells. In healthy cells, nuclear material divides to form two separate cells, each surrounded by a cell membrane. In UNC45A-deficient cells, the nuclear material struggle to divide and the division into two cells fail.

Dr. Chadli said that inhibiting UNC45A holds tremendous potential in the fight against solid tumors since its role in proliferation does not appear to be necessary for the survival of healthy cells. He added that how to inhibit its tumoral role apart from its normal functions is the topic of future studies that would improve the scientists' understanding of this molecular machine and how to harness its potential clinical application.

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