Advanced Science
·
2025
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IF 14.1
Yijing Zhang,Han Gao,Aiwen Tang,Haiwen Lyu,Zongmin Fan,Jiahui Guo,Yuzhi Wang,Hairong Yi,Qihao Pan,Haidan Luo,Baifu Qin,Boyu Zhang,Xiangqi Meng,Qingxin Liu,Mong-Hong Lee
Pancreatic ductal adenocarcinoma (PDAC) is a fatal cancer with poor prognosis. COP9 signalosome subunit 6 (CSN6), a key regulator of different E3 ubiquitin ligases, plays oncogenic roles in various cancers. However, its function in PDAC remains elusive. Here, this demonstrates that human PDAC tumors expressing high levels of CSN6 present with poor prognosis and gemcitabine resistance. Conditional knockout (KO) of CSN6 hinders tumor formation in a KPP spontaneous PDAC mouse model. Proteomic analysis indicates that CSN6 promotes ribosome biogenesis by activating rDNA transcription and protein synthesis. Mechanistically, CSN6 antagonizes DDB1-CUL4 associated factor 1 (DCAF1)-mediated ubiquitination of Nucleophosmin (NPM1), thereby promoting NPM1-orchestrated ribosome biogenesis. In line with CSN6-mediated gemcitabine resistance, CSN6-NPM1 axis enhances ribosome biogenesis, thereby promoting translation of gemcitabine resistance genes, including Cytidine deaminase (CDA), Ribonucleotide reductase subunit M1/2 (RRM1/2). Significantly, combining gemcitabine with NPM1 inhibitor NSC348884 synergistically suppresses CSN6-high pancreatic cancer xenografts. Clinically, CSN6 expression positively correlates with NPM1 in PDAC tissues, and their concurrent high expression is significantly associated with poor clinical outcomes. This study characterizes CSN6 as an oncogenic protein that promotes NPM1 stabilization by interacting with DCAF1, thereby enhancing ribosome biogenesis and cellular resistance to gemcitabine in PDAC. NPM1 may serve as a therapeutic target for CSN6 high PDAC that exhibits gemcitabine drug resistance.
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产品关联
DOI
PubMed
高影响因子
Signal Transduction and Targeted Therapy
·
2023
·Vol. 8
·期 1
·1-21
·
IF 39.3
Wei Wenxia,Qin Baifu,Wen Weijie,Zhang Boyu,Luo Haidan,Wang Yuzhi,Xu Hui,Xie Xiaoshan,Liu Sicheng,Jiang Xin,Wang Mengan,Tang Qin,Zhang Jiayu,Yang Runxiang,Fan Zongmin,Lyu Haiwen,Lin Junzhong,Li Kai,Lee Mong-Hong
Continuous de novo fatty acid synthesis is required for the biosynthetic demands of tumor. FBXW7 is a highly mutated gene in CRC, but its biological functions in cancer are not fully characterized. Here, we report that FBXW7β, a FBXW7 isoform located in the cytoplasm and frequently mutated in CRC, is an E3 ligase of fatty acid synthase (FASN). Cancer-specific FBXW7β mutations that could not degrade FASN can lead to sustained lipogenesis in CRC. COP9 signalosome subunit 6 (CSN6), an oncogenic marker of CRC, increases lipogenesis via interacting with and stabilizing FASN. Mechanistic studies show that CSN6 associates with both FBXW7β and FASN, and antagonizes FBXW7β’s activity by enhancing FBXW7β autoubiquitination and degradation, which in turn prevents FBXW7β-mediated FASN ubiquitination and degradation, thereby regulating lipogenesis positively. Both CSN6 and FASN are positively correlated in CRC, and CSN6-FASN axis, regulated by EGF, is responsible for poor prognosis of CRC. The EGF-CSN6-FASN axis promotes tumor growth and implies a treatment strategy of combination of orlistat and cetuximab. Patient-derived xenograft experiments prove the effectiveness of employing orlistat and cetuximab combination in suppressing tumor growth for CSN6/FASN-high CRC. Thus, CSN6-FASN axis reprograms lipogenesis to promote tumor growth and is a target for cancer intervening strategy in CRC.
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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药理学
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DOI
PubMed
高影响因子
EXPERIMENTAL CELL RESEARCH
·
2018
·
IF 3.309
Yanting Zhu,Fangwei Li,Wenhua Shi,Cui Zhai,Jian Wang,Xin Yan,Qingting Wang,Qianqian Zhang,Lan Yang,Li Gao,Manxiang Li
Up-regulation of mammalian COP9 signalosome subunit 6 (CSN6) and consequent reduction of SCF ubiquitin ligase substrate receptor β-transduction repeat-containing protein (β-TrCP) have been shown to be associated with cancer cells proliferation . However, it is unclear whether CSN6 and β-TrCP are also involved in PDGF-induced pulmonary arterial smooth muscle cells (PASMCs) proliferation. This study aims to address this issue and further explore its potential mechanisms. Our results indicated that PDGF phosphorylated Akt, stimulated PASMCs proliferation; while inhibition of PDGF receptor (PDGFR) by imatinib prevented these effects. PDGF further up-regulated CSN6 protein expression , this was accompanied with β-TrCP reduction and increase of Cdc25A. Inhibition of PDGFR/PI3K/Akt signaling pathway reversed PDGF-induced such changes and cell proliferation. Prior transfection of CSN6 siRNA blocked PDGF-induced β-TrCP down-regulation, Cdc25A up-regulation and cell proliferation. Furthermore, pre-treatment of cells with MG-132 also abolished PDGF-induced β-TrCP reduction, Cdc25A elevation and cell proliferation. In addition, pre-depletion of Cdc25A by siRNA transfection suppressed PDGF-induced PASMCs proliferation. Taken together, our study indicates that up-regulation of CSN6 by PDGFR/PI3K/Akt signaling pathway decreases β-TrCP by increasing its ubiquitinated degradation, and thereby increases the expression of Cdc25A, which promotes PDGF-induced PASMCs proliferation.
研究领域:
细胞生物学
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分子生物学
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药理学
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DOI
PubMed
高影响因子
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