CRL3Keap1 E3 ligase facilitates ubiquitin-mediated degradation of oncogenic SRX to suppress colorectal cancer progression

Abstract

The antioxidant protein sulfiredoxin-1 (SRX) is an oncogenic factor that promotes tumor progression, but the regulatory mechanism underlying SRX degradation remains to be understood. Herein, we report that Keap1, the substrate-specific adapter of CRL3 complex, specifically binds and promotes the ubiquitin-mediated degradation of SRX at residue K61. Keap1 knockdown accumulates SRX, which in turn facilitates colorectal cancer (CRC) metastasis by activating the activator protein-1/matrix metalloproteinase 9 (AP-1/MMP9) pathway. CRC-associated Keap1 mutants within the BACK domain lose the capability to ubiquitinate SRX and instead promote CRC metastasis. Moreover, inactivation of Keap1 facilitates CRC tumorigenesis and metastasis in mouse models of tumor xenograft due to SRX accumulation. Clinical sample analysis reveals that Keap1 is downregulated while SRX is overexpressed in CRC, which correlates with poor prognosis. Our findings elucidate a mechanism by which CRL3^Keap1 ubiquitin ligase degrades SRX to suppress CRC progression, indicating that the Keap1-SRX axis will guide the targeted therapy towards CRC.