Hypercholesterolemia Increases the Risk of Colorectal Cancer by a Tet-1-Dependent HSC-Autonomous Mechanism

The annual, age-standardized colorectal cancer (CRC) incidence rate has decreased by 46% from its peak in 1985. However, this long-standing decline in cases of CRC slowed due mainly to an increase in incidence in individuals younger than 50 years of age. For those less than 50 years of age, CRC is the leading cause of cancer deaths in men and the second in women. At least half of all cases of young-onset CRC are linked to lifestyle risk factors, including obesity. Hypercholesterolemia, a common metabolic disorder in obese people, has been shown to increase the risk of colorectal cancer, but the mechanism is unknown. We will show that hypercholesterolemia increases the incidence and pathological severity of colorectal cancer by inducing an oxidant stress-dependent hematopoietic stem cell-autonomous mechanism. The oxidized-LDL increase in HSC oxidant stress initiates a signaling pathway that culminates in the increased expression of miR101c that downregulates Tet1. This downregulation of Tet1 reduces the expression of the genes critical to the production and cytotoxicity of natural killer T cells and T cells, thereby impairing cancer immunosurveillance against colorectal cancer. This reveals a novel mechanism where a metabolic disorder induces epigenetic reprogramming of natural killer T cells and γδT gene expression within hematopoietic stem cells.