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Salk scientists identify novel regulator of key gene expression in cancer

Michal Krawczyk and Beverly Emerson

The COX-2 gene mediates inflammation, which in most cases helps our bodies eliminate pathogens and damaged cells. But inflammation also has a dark side: it aids growth and spread of tumors in the early stages of cancer. By learning more about how COX-2 is affected, scientists may be able to provide a potential target for future cancer treatment.

Now, a team in the lab of Beverly Emerson has identified a key genetic switch, a string of nucleotides dubbed a long non-coding RNA (lncRNA), that acts as an on/off switch for the COX-2 gene. The function of lncRNAs is not well understood, but evidence increasingly points to their role in regulating gene expression, as they are found overexpressed in esophageal, colorectal and breast cancers.

“Deciphering the mechanism of COX-2 gene regulation is of great clinical interest,” says Emerson, holder of the Edwin K. Hunter Chair. “COX-2 is instrumental in the development of several types of cancer, including colon, breast and prostate cancer. Strategies that specifically modulate COX-2 activity could be an attractive treatment approach.”

Using human mammary epithelial cells, Emerson and senior scientist Michal Krawczyk discovered that an lncRNA called PACER kicks a molecule called p50 off the COX-2 gene, causing COX-2 to go into overdrive. This is the first time scientists have shown that non-coding RNAs must be activated in order to squelch the activity of p50, a gene repressor. In turn, says Krawczyk, blocking p50 promotes the assembly of molecular activators of gene expression, which ramp up COX-2 activity.

The scientists were also surprised to note an additional potential role for PACER-induced COX-2 activation in cancer. Early in the disease process, instead of activating the immune system to clear malignant cells from the body, COX-2 aids the growth and spread of tumors. In later stages of disease, however, Krawczyk says cancer cells often shut off COX-2 activity, as if at that stage COX-2 is no longer beneficial for tumor growth because it exposes spreading tumor cells to the immune system. That presents the opportunity to trigger COX-2 expression via PACER in late-stage cancers to aid immune system clearance of metastatic cells.

“This could be a potential treatment for late-stage cancers,” says Krawczyk. “We could possibly use small molecules to reactivate COX-2 activity, or perhaps even supply PACER itself, to fight the disease.” The findings of the study were published in eLife.