Obesity will soon surpass smoking as the most preventable cause of cancer. Hypercholesterolemia, a common comorbidity of obesity, has been shown to increase cancer risk, especially colorectal cancer. However, the mechanism by which hypercholesterolemia or any metabolic disorder increases cancer risk remains unknown. In this study, we show that hypercholesterolemia increases the incidence and pathological severity of colorectal neoplasia in two independent mouse models. Hypochlosterolemia induced an oxidant-stress dependent increase in miR101c which downregulated Tet1 in hematopoietic stem cells (HSC), resulting in reduced expression of genes critical to natural killer T cell (NKT) and γδ T cell differentiation. These effects reduced the number and function of terminally differentiated NKT and γδ T cells in the thymus, the colon submucosa, and during early tumorigenesis. These results suggest a novel mechanism by which a metabolic disorder induces epigenetic changes to reduce lineage priming of HSC towards immune cells, thereby compromising immunosurveillance against cancer.
- Received July 24, 2016.
- Revision received January 20, 2017.
- Accepted February 24, 2017.
- Copyright ©2017, American Association for Cancer Research.