The USP11/Nrf2 positive feedback loop promotes colorectal cancer progression by inhibiting mitochondrial apoptosis

• Published in: Cell death & disease 2024-12, Vol.15 (12), p.873-12
• Main Authors: Lu, Yuanyuan, wei, Wanhui, Li, Mengting, Chen, Danyang, Li, Wenjie, Hu, Qian, Dong, Shouquan, Liu, Lan, Zhao, Qiu
• Format: Article
• Language: English
• Subjects: 38; 38/89; 64; 64/60; 692/699/1503; 692/699/67/1504/1885; Animals; Antibodies; Antioxidants; Apoptosis; Biochemistry; Biomedical and Life Sciences; Cancer; Cell Biology; Cell Culture; Cell Line, Tumor; Colorectal cancer; Colorectal carcinoma; Colorectal Neoplasms - genetics; Colorectal Neoplasms - metabolism; Colorectal Neoplasms - pathology; Disease Progression; Feedback; Feedback, Physiological; Female; Gene Expression Regulation, Neoplastic; Gene regulation; HCT116 Cells; Homeostasis; Humans; Immunology; Life Sciences; Male; Malignancy; Mice; Mice, Inbred BALB C; Mice, Nude; Mitochondria; Mitochondria - metabolism; NF-E2-Related Factor 2 - metabolism; NRF2 protein; Oxidative stress; Post-transcription; Proteasomes; Reactive oxygen species; Reactive Oxygen Species - metabolism; Signal Transduction; Therapeutic targets; Thiolester Hydrolases - genetics; Thiolester Hydrolases - metabolism
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/s41419-024-07188-2

Abnormal antioxidant capacity of cancer is closely related to tumor malignancy. Modulation of oxidative stress status is a novel anticancer therapeutic target. Nrf2 is a key regulator of various antioxidant enzymes, but the mechanism of its deubiquitination remains largely unclear. This study unveiled that Nrf2 received post-transcriptional regulation from a proteasome-associated deubiquitinating enzyme, USP11, in colorectal cancer (CRC). It was found that USP11 was overexpressed in CRC tissues acting as an oncogene by inhibiting mitochondrial apoptosis, and USP11 managed to maintain balance in the production and elimination of reactive oxygen species (ROS). Mechanistically, we identified a feedback loop between USP11 and Nrf2 maintaining the redox homeostasis. USP11 stabilized Nrf2 by deubiquitinating and protecting it from proteasome-mediated degradation. Interestingly, we also map that Nrf2 could bind to the antioxidant reaction element (ARE) in the USP11 promoter to promote its transcription. Hence, USP11/Nrf2 positive feedback loop inhibited mitochondrial apoptosis of CRC cells by activating Nrf2/ARE signaling pathway, thus promoting CRC progression. Schematic diagram of the mechanism by which USP11/Nrf2 positive feedback loop inhibited mitochondrial apoptosis in CRC cells . This study found that USP11 was highly expressed in colorectal cancer (CRC) tissue and was associated with poor prognosis. In CRC, the inhibition of USP11 expression could promote the ubiquitination degradation of Nrf2, thereby inhibiting the Nrf2/ARE signaling pathway. This led to an increase in reactive oxygen species in the cell, causing mitochondrial apoptosis. In addition, Nrf2 could bind to the promoter region of USP11 to promote its transcription, both of which formed positive feedback loop.