DCLK1 Enhances LIPG-mediated Fatty Acid Metabolism and Cancer Malignancy in Colorectal Cancer

Abstract

Purpose: Cancer therapy is hampered by Cancer stem-like cells (CSCs). A CSC marker called Doublecortin-like kinase 1 (DCLK1) contributes to the aggressiveness of colorectal cancer (CRC). In this study, we sought to investigate the role of DCLK1 and the precise mechanism in the development of CRC malignancy. Methods: To identify the influences of DCLK1 on CRC malignancy, RNA sequencing was used to explore the downstream target of DCLK1. Next, biological and molecular experiments were conducted to uncover the mechanism in CRC cells. Results: Bioinformatics analyses from a clinical genomic database of CRC suggested that DCLK1-driven CRC aggressiveness was significantly associated with fatty acid metabolism pathways. Mechanistically, we identified Endothelial lipase (LIPG), a downstream target of DCLK1, which enhanced the fatty acid uptake and fatty acid oxidation rate. Consistent with this finding, DCLK1 promotes fatty acid uptake and fatty acid oxidation rates by enhancing the expression of LIPG, which in turn increases ATP production. These events accelerated cancer metastasis while also enhancing CRC development and aggressiveness. Conclusions: DCLK1 provides adequate materials and energy to CRC cells for their development and metastasis via modulating the LIPG-mediated fatty acid metabolism reprogramming.