Sulfiredoxin promotes colorectal cancer cell invasion and metastasis through a novel mechanism of enhancing EGFR signaling

Sulfiredoxin (SRXN1/Srx) is a multifunction enzyme with a primary antioxidant role of reducing the overoxidized inactive form of peroxiredoxins (Prxs). The function and mechanisms of Srx in cancer development are not well understood. Here, Srx is preferentially expressed in human colorectal cancer cells but not in normal colon epithelial cells. Loss-of-function studies demonstrate that knockdown of Srx in poorly differentiated colorectal cancer cells not only leads to the inhibition of colony formation and cell invasion in vitro, but also reduces tumor xenograft growth and represses metastasis to distal organs in a mouse orthotopic implantation model. Notably, exactly opposite effects were observed in gain-of-function experiments when Srx was ectopically expressed in well-differentiated colorectal cancer cells. Mechanistically, expression of Srx enhances the activation of MAPK signaling through increasing the C-Terminal tyrosine phosphorylation levels of EGFR. This function of Srx is mediated through its inhibition of EGFRacetylation at K1037, a novel posttranslational modification of EGFR in human colorectal cancer cells identified by liquid chromatography-electrospray ionization-Tandem mass spectrometry (LC/ESI/MS-MS) proteomic analysis. Furthermore, abolishment of K1037 acetylation in human colorectal cancer cells by site-specific mutagenesis leads to sustained activation of EGFR-MAPK signaling. Combined, these data reveal that Srx promotes colorectal cancer cell invasion and metastasis through a novel mechanism of enhancing EGFR signaling. Implications: Sulfiredoxin is a critical oncogenic protein that can be used as a molecular target to develop therapeutics for patients with metastatic colorectal cancer.