Lu Yuanyuan, Wei Wanhui, Li Mengting, Chen Danyang, Li Wenjie, Hu Qian, Dong Shouquan, Liu Lan, Zhao Qiu
Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, China.
Hubei Clinical Center and Key Lab of Intestinal and Colorectal Diseases, Wuhan, China.
Cell Death Dis. 2024 Dec 1;15(12):873. 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.
癌症异常的抗氧化能力与肿瘤恶性程度密切相关。调节氧化应激状态是一种新型的抗癌治疗靶点。Nrf2是多种抗氧化酶的关键调节因子，但其去泛素化机制仍不清楚。本研究揭示，在结直肠癌（CRC）中，Nrf2受到一种蛋白酶体相关去泛素化酶USP11的转录后调控。研究发现，USP11在CRC组织中过表达，通过抑制线粒体凋亡发挥癌基因作用，并且USP11能够维持活性氧（ROS）产生与清除的平衡。机制上，我们确定了USP11和Nrf2之间维持氧化还原稳态的反馈回路。USP11通过去泛素化并保护Nrf2免受蛋白酶体介导的降解来使其稳定。有趣的是，我们还发现Nrf2可以结合USP11启动子中的抗氧化反应元件（ARE）以促进其转录。因此，USP11/Nrf2正反馈回路通过激活Nrf2/ARE信号通路抑制CRC细胞的线粒体凋亡，从而促进CRC进展。USP11/Nrf2正反馈回路抑制CRC细胞线粒体凋亡的机制示意图。本研究发现USP11在结直肠癌（CRC）组织中高表达，且与预后不良相关。在CRC中，抑制USP11表达可促进Nrf2的泛素化降解，从而抑制Nrf2/ARE信号通路。这导致细胞内活性氧增加，引发线粒体凋亡。此外，Nrf2可结合USP11的启动子区域促进其转录，二者形成正反馈回路。
