STC2 promotes colorectal cancer progression via c-Myc-mediated glycolysis and the PI3K/AKT/mTOR pathway

While growing evidence highlights the significance of metabolic reprogramming in colorectal cancer (CRC), the exact mechanisms behind these changes remain unclear. This study sought to identify key metabolic regulators and clarify their downstream pathways in CRC progression.

Three independent CRC datasets were subjected to differential expression analysis and lactylation-related gene screening, resulting in candidate genes, among which the STC2 gene was prioritized. STC2 expression was first assessed in HIEC-6, Caco-2, LoVo, SW480, and HCT116 cells. STC2 knockdown and overexpression models were established in HCT116 cells to examine their effects on proliferation, migration, invasion, and apoptosis. Lactate production and glucose uptake tests, Western blot, chromatin immunoprecipitation (ChIP), and Quantitative real-time polymerase chain reaction (qRT-PCR) were utilized to delineate the molecular mechanisms. A xenograft mouse model was applied to validate in vivo effects.

STC2 levels in CRC cells are significantly higher than in normal intestinal cells. STC2 knockdown inhibits cell growth and glycolysis, but its overexpression significantly enhances these activities. Mechanistically, STC2 enhanced c-Myc activity through the PI3K/AKT/mTOR pathway, which upregulated GLUT1 and LDHA to maintain glycolytic flux. ChIP analysis showed that c-Myc occupancy on the GLUT1 and LDHA promoters was increased under STC2 overexpression, whereas binding was reduced upon STC2 silencing. In vivo, STC2 overexpression accelerated tumor growth and enhanced glycolysis in a xenograft mouse model.

These findings highlight STC2 as a key regulator of CRC progression, which regulates c-Myc-driven glycolysis through the PI3K/AKT/mTOR pathway. Targeting STC2 or its downstream metabolic effectors may provide new therapeutic strategies for CRC management.