CANCER RESEARCH
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2025
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IF 16.6
Zhou Hai-Meng,Liu Yi,Shi Feng,Qiu Hao-Wen,Li Le,Shu Qi-Peng,Liu Yu-Ying,Wang Bai-Qi,Gao Meng,Du Run-Lei,Ke Shao-Bo,Zhang Xiao-Dong
Ferroptosis, a form of regulated cell death driven by iron-dependent lipid peroxidation, plays a crucial role in colorectal cancer (CRC) progression and therapeutic response. The NRF2 pathway is one of the critical axes in ferroptosis regulation, which governs oxidative stress resistance and iron homeostasis through its downstream targets, including HMOX1, SLC7A11, and others. However, HMOX1 and SLC7A11 exhibit contrasting roles in ferroptosis, with HMOX1 promoting ferroptosis via iron accumulation and lipid peroxidation, while SLC7A11 inhibits ferroptosis by enhancing antioxidant defenses. Here, we identified CLK2 as a key regulator of the delicate balance of the opposing effects of HMOX1 and SLC7A11. CLK2 stabilized KEAP1 to suppress NRF2 activity, resulting in the downregulation of HMOX1 and SLC7A11. Simultaneously, CLK2 downregulated p53, thereby relieving p53-mediated repression of SLC7A11. The dual regulation by CLK2 disrupted the balance between HMOX1 and SLC7A11, leading to excessive activation of HMOX1 in the absence of CLK2, ultimately sensitizing CRC cells to ferroptosis. Additionally, CLK2 promoted CRC proliferation and tumorigenesis in patient-derived organoids, cell lines, and mouse models. Furthermore, combining the ferroptosis inducer Erastin with Oxaliplatin significantly enhanced anti-tumor efficacy in CLK2-deficient xenograft models. Together, this study establishes CLK2 as a critical inhibitor of ferroptosis via the KEAP1/NRF2/HMOX1 and p53/SLC7A11 axes, supporting its potential as a therapeutic target for CRC.
研究领域:
癌症生物学
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分子生物学
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细胞死亡
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信号转导
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肿瘤学
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药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
CANCER LETTERS
·
2023
·
IF 9.7
Tian-Jiao Li,Kai-Zhou Jin,Hong-Yu Zhou,Zhen-Yu Liao,Hui-Ru Zhang,Sai-Meng Shi,Meng-Xiong Lin,Shou-Jie Chai,Qing-Lin Fei,Long-Yun Ye,Xian-Jun Yu,Wei-Ding Wu
Pancreatic ductal adenocarcinoma (PDAC) is extremely malignant with limited treatment options. Deubiquitinases (DUBs), which cleave ubiquitin on substrates, can regulate tumor progression and are appealing therapeutic targets, but there are few related studies in PDAC. In our study, we screened the expression levels and prognostic value of USP family members based on published databases and selected USP10 as the potential interventional target in PDAC. IHC staining of the PDAC microarray revealed that USP10 expression was an adverse clinical feature of PDAC. USP10 promoted tumor growth both in vivo and in vitro in PDAC. Co-IP experiments revealed that USP10 directly interacts with PABPC1. Deubiquitination assays revealed that USP10 decreased the K27/29-linked ubiquitination level of the RRM2 domain of PABPC1. Deubiquitinated PABPC1 was able to couple more CLK2 mRNA and eIF4G1, which increased the translation efficiency. Replacing PABPC1 with a mutant that could not be ubiquitinated impaired USP10 knock-down-mediated tumor suppression in PDAC. Targeting USP10 significantly delayed the growth of cell-derived xenograft and patient-derived xenograft tumors. Collectively, our study first identified USP10 as the DUB of PABPC1 and provided a rationale for potential therapeutic options for PDAC with high USP10 expression.
研究领域:
肿瘤学
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分子生物学
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癌症生物学
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转化医学
✓ 已验证
DOI
PubMed
高影响因子
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