GATA6 enhances the stemness of human colon cancer cells by creating a metabolic symbiosis through upregulating LRH‐1 expression

Cancer stem cells play critical roles in tumor initiation, progression, and relapse. Since we previously found that GATA6 promotes the stemness in HCT‐116 and HT‐29 human colorectal cancer (CRC) cells, we aimed to identify the downstream mediator(s) of the stemness‐stimulating effect of GATA6 herein. LRH‐1 was found as a direct target of GATA6 and its upregulation promoted the stemness in both HCT‐116 and HT‐29 cells. Subsequently, hypoxia‐inducible factor‐1α (HIF‐1α) was identified as a direct target of LRH‐1 and its expression level and activity were significantly elevated in the LRH‐1‐overexpressing clones established from the aforementioned two CRC lines. Accordingly, the expression levels of several HIF‐1α targets were also markedly increased, resulting in a stronger glycolysis associated with dramatic elevations of the lactate levels in these cells. Strikingly, higher mitochondrial activities were also found in these clones which might be attributed to the increase of PGC‐1α stimulated by the lactate uptaken through the upregulated MCT‐1. Finally, significant increases in the self‐renewal ability, intracellular radical oxygen species levels and mitochondrial mass were detected in the CD133+/CD44+ subpopulations isolated from CRC cells regardless of their LRH‐1 expression levels. Together, our results suggest a novel metabolic symbiosis between different colorectal cancer stem cell subpopulations critical for maintaining their mutual stemness.
Our observations demonstrate a reverse Warburg effect in human colorectal cancer stem cells (CRCSCs) because the expression levels and activity of hypoxia‐inducible factor‐1α are markedly increased by LRH‐1 upregulation resulted from GATA6 overexpression in the majority of colorectal cancer (CRC) cells which undergo aerobic glycolysis to proliferate rapidly and, in the meantime, generate large amount of lactate that can be uptaken by another subset of CRC cells for mitochondrial oxidative phosphorylation. In this manner, metabolic symbiosis and energy transfer are maintained between two CRCSC subpopulations.