PHARMACOLOGICAL RESEARCH
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2021
·
IF 7.658
Senfeng Xiang,Xiaoxian Shi,Pengfei Chen,Yifan Chen,Shaowei Bing,Xizhi Jin,Ji Cao,Jinhu Wang,Bo Yang,Xuejing Shao,Qiaojun He,Meidan Ying
Targeted therapy has become increasingly important and indispensable in cancer therapy. Cullin3-RING ligases (CRL3) serve as essential executors for regulating protein homeostasis in cancer development, highlighting that CRL3 might be promising targets in various cancer treatment. However, how to design new targeted therapies by disrupting the function of CRL3 is poorly understood. Here, we focus on the substrate adaptors of CRL3, and carry out a systematical research on the function of Kelch-like (KLHL) family proteins. We have identified twenty-four KLHL proteins with function of tumor promotion and thirteen KLHL proteins with high clinical significance on cancer therapy. Furthermore, we have clarified the novel biological function of KLHL13 as a vital factor that contributes to malignant progression in lung cancer. Taken together, our findings reveal multiple potential therapeutical targets and provide evidence for targeting CRL3 via KLHL substrate adaptors for cancer therapy.
研究领域:
肿瘤学
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分子生物学
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药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ONCOGENE
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2025
·
IF 7.3
Wei Xiaosong,Wang Beibei,Yang Yang,Fang Zhiwei,Yi Chengzhi,Zhang Liuhui,Fan Xin,Tang Dongdong,Zhang Lirong,Yang Xiaoming,Song Dongkui
Zinc finger protein 24 (ZNF24) is a conserved multifunctional transcription factor associated with tumorigenesis, but its function in bladder carcinogenesis remains unclear. Herein, the expression of ZNF24 was decreased in bladder cancer (BC) cells and tissues, and patients with higher expression of ZNF24 had a better prognosis. Doxycycline-induced overexpression and knockdown of ZNF24 identified its anti-proliferative and anti-metastasis role in BC in vitro and in vivo. The potential genes for the anti-cancer role of ZNF24, involving transcriptional regulation of several factors, such as dual-specificity phosphatase 1 and squalene epoxidase. E2 conjugating enzyme UBC9 and small ubiquitin-like modifier (SUMO) 1 were found to interact with ZNF24, suggesting that ZNF24 may be SUMOylated. Consistent with the expression, ZNF24 SUMOylation levels were decreased in BC cells and tissues. Pan-SUMOylation inhibition promoted protein degradation of ZNF24. UBC9 SUMOylated ZNF24 at Lys-27 (K27) site with SUMO1 modification and the K27 mutation of ZNF24 greatly damaged the protein stability of ZNF24. Cullin 3 (CUL3), a E3 ubiquitin ligase, was responsible for the degradation of ZNF24. ZNF24 SUMOylation prevented CUL3-mediated protein degradation of ZNF24. Overall, the crosstalk between the SUMOylation and ubiquitination of ZNF24 may be a novel regulatory mechanism to block tumorigenesis and development of BC.
研究领域:
肿瘤学
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分子生物学
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细胞生物学
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产品关联
DOI
PubMed
高影响因子
Antioxidants
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2020
·Vol. 9
·期 9
·783
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IF 5.014
Bowen Sun,Xifan Wang,Xiaoxue Liu,Longjiao Wang,Fazheng Ren,Xiaoyu Wang,Xiaojing Leng
Chronic kidney disease (CKD) is characterized by the accumulation of protein-bound uremic toxins (PBUTs), which play a pathophysiological role in renal fibrosis (a common pathological process resulting in CKD progression). Accumulation of the PBUT hippuric acid (HA) is positively correlated with disease progression in CKD patients, suggesting that HA may promote renal fibrosis. Oxidative stress is the most important factor affecting PBUTs nephrotoxicity. Herein, we assessed the ability of HA to promote kidney fibrosis by disrupting redox homeostasis. In HK-2 cells, HA increased fibrosis-related gene expression, extracellular matrix imbalance, and oxidative stress. Additionally, reactive oxygen species (ROS)-mediated TGFβ/SMAD signaling contributed to HA-induced fibrotic responses. HA disrupted antioxidant networks by decreasing the levels of nuclear factor erythroid 2-related factor 2 (NRF2), leading to ROS accumulation and fibrotic responses, as evidenced by NRF2 activation and knockdown. Moreover, NRF2 levels were reduced by NRF2 ubiquitination, which was regulated via increased interactions of Kelch-like ECH-associated protein 1 with Cullin 3 and NRF2. Finally, renal fibrosis and redox imbalance promoted by HA were confirmed in rats. Importantly, sulforaphane (NRF2 activator) reversed HA-promoted renal fibrosis. Thus, HA promotes renal fibrosis in CKD by disrupting NRF2-driven antioxidant system, indicating that NRF2 is a potential therapeutic target for CKD.Keywords:hippuric acid;protein-bound uremic toxin;renal fibrosis;oxidative stress;antioxidation;NRF2;NRF2 ubiquitination
研究领域:
肾病学
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药理学
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分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
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