CUL7-mediated KEAP1 ubiquitination promotes the progression of colon cancer via NRF2 signaling.

Cullin7 (CUL7) mediates cancer progression across multiple cancer types through its regulatory role in protein ubiquitination. However, the biological function and molecular mechanisms underlying CUL7 in colon cancer remain poorly defined. Here, we demonstrate that high CUL7 expression correlates with poor prognosis in patients. Ablation of CUL7 inhibited cell proliferation and migration in colon cancer cells, whereas CUL7 overexpression exhibited oncogenic properties. Moreover, Cul7-deplete mice exhibit a lower level of tumor growth. Mechanistically, CUL7 interacts with Kelch-like ECH-associated protein 1 (KEAP1) and catalyzes K29- and K48-linked polyubiquitination to promote its proteasomal degradation, which is crucial for NRF2 signaling. This leads to the decline of reactive oxygen species (ROS) and promotion of cancer growth. Importantly, the C-terminus of CUL7 is a crucial for governing KEAP1 stability and orchestrating antioxidant defense and cell growth. Clinical analysis identifies an inverse correlation between CUL7 and KEAP1 expression, and a positive correlation between CUL7 and NRF2 levels in human colon cancer. Our findings indicate that CUL7 mediates NRF2 signaling through promoting the KEAP1 ubiquitination, a mechanism that is integral to colon cancer progression. Collectively, these results establish CUL7 as a potential therapeutic target for colon cancer.