The stem cell gene ABCB5 regulates DNA methylation in colorectal cancer

Abstract

ABCB5 marks cancer stem cell subpopulations in diverse human malignancies and is responsible for several features of tumor aggressiveness, including therapeutic drug resistance and metastasis. Exactly how these pleiotropic functions are exerted is currently unknown. We hypothesized that ABCB5 might regulate an epigenetic DNA hydroxymethylation pattern, i.e. loss of 5‐hydroxymethylcytosine (5‐hmC), which has previously been shown to correlate with cancer aggression in diverse malignancies, including colorectal cancer. To test this hypothesis, we examined the functional relationship between ABCB5 expression and 5‐hmC levels, utilizing four distinct mouse and human colorectal cancer models in which ABCB5 function was either genetically ablated or blocked by anti‐ABCB5 monoclonal antibody. In support of our hypothesis, we found that both genetic and antibody‐mediated ABCB5 blockade resulted in restoration of 5‐hmC levels and diminished tumor aggressiveness features. These results suggest a novel role of ABCB5 as a regulator of colorectal cancer aggressiveness through epigenetic regulation, with important implications for novel therapeutic strategies in this highly prevalent human malignancy.