Control of Paneth Cell Fate, Intestinal Inflammation, and Tumorigenesis by PKCλ/ι

Yuki Nakanishi, Miguel Reina-Campos, Naoko Nakanishi, Victoria Llado, Lisa Elmen, Scott Peterson, Alex Campos, Surya K. De, Michael Leitges, Hiroki Ikeuchi, Maurizio Pellecchia, Richard S. Blumberg, Maria T. Diaz-Meco, and Jorge Moscat

Naoko Nakanishi, Yuki Nakanishi, Maria Diaz-Meco, Miguel Reina Camps, and Jorge Moscat

From left: Naoko Nakanishi, Yuki Nakanishi, Maria Diaz-Meco, Miguel Reina Campos, Jorge Moscat.

The intestine is protected by specialized cells, called Paneth cells, that secrete antimicrobial peptides. We found that maintaining normal numbers of Paneth cells requires a kinase termed protein kinase Cλ/ι (PKCλ/ι). Notably, the amount of PKCλ/ι decreases as intestinal inflammation gets worse in patients of Crohn’s disease. We also discovered a way to prevent Paneth cell loss by inhibiting a protein called EZH2, which is regulated by PKCλ/ι and that could be a new therapeutic strategy for inflammatory bowel disease that include Crohn’s disease and ulcerative colitis and that affects 1.4 million people in the U.S. These chronic conditions are often debilitating, as they cause unpredictable abdominal pain and diarrhea. Because current medications only help control symptoms and not the underlying disease, 70% of Crohn’s patients and 30% of those with colitis must eventually undergo surgery. In addition, IBD increases risk of intestinal cancer by as much as 60%. Therefore, we also examined the effect of PKCλ/ι on tumor formation and found that that in the intestine, PKCλ/ι is a tumor suppressor by maintaining the levels of EZH2 low and consequently protecting the intestine of inflammation. Our study used an in vitro model—‘mini guts’ in a dish—to show that blocking EZH2 helps return the number of Paneth cells to normal. This demonstrates that inhibiting EZH2 could be a new way to slow the progression of IBD. Importantly, our laboratory verified the relevance of their findings in mouse models of intestinal inflammation and cancer, as well as by analyzing biopsy samples from 30 patients with Crohn’s disease. Interestingly, EZH2 inhibitors are currently being developed by the pharmaceutical industry to treat other cancers, so they could be tested for IBD relatively soon, at least initially in preclinical studies.

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