CUL7-mediated KEAP1 ubiquitination promotes the progression of colon cancer via NRF2 signaling.
Shi Le, Shi Feiyu, Zhang Yue, Liu Ruichen, Liu Quanyu, Zhang Shuangxi, Wang Zhen, Su Wu, Gao Dan, Liu Yi, Dai Xiangpeng, Guo Hui, Liu Jiankang, She Junjun, Long Jiangang
Abstract
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.
Key Findings
- High CUL7 expression correlates with poor prognosis in colon cancer patients.
- CUL7 promotes colon cancer progression by mediating ubiquitination and degradation of KEAP1, leading to activation of NRF2 signaling.
- CUL7 depletion inhibits tumor growth and reduces cancer cell proliferation and migration.
- CUL7 regulates antioxidant defense and cell growth through its C-terminus domain affecting KEAP1 stability.
- Clinical data shows inverse correlation between CUL7 and KEAP1 and positive correlation between CUL7 and NRF2 in human colon cancer.
Clinical Significance
CUL7 represents a potential therapeutic target in colon cancer by modulating NRF2 signaling via KEAP1 ubiquitination, offering a novel approach for drug development against tumor progression.
Citation
Shi Le, Shi Feiyu, Zhang Yueet al.. CUL7-mediated KEAP1 ubiquitination promotes the progression of colon cancer via NRF2 signaling. Cell death & disease. 2026-Jun-08.