Positive feedback of SuFu negating protein 1 on Hedgehog signaling promotes colorectal tumor growth.
Positive feedback of SuFu negating protein 1 on Hedgehog signaling promotes colorectal tumor growth.
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SuFu否定蛋白1对Hedgehog信号的正反馈促进结直肠肿瘤生长
DOI：
10.1038/s41419-021-03487-0
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发表时间：
2021-02-19
影响因子：
9
通讯作者：
Luo S
中科院分区：
文献类型：
--
作者：
Yan Z;Cheng M;Hu G;Wang Y;Zeng S;Huang A;Xu L;Liu Y;Shi C;Deng L;Lu Q;Rao H;Lu H;Chen YG;Luo S
Hedgehog（Hh）信号在胚胎发生和组织稳态中起着关键作用，其失调与肿瘤生长有关。肿瘤抑制因子SuFu通过阻止Gli的核转位和抑制细胞增殖来抑制Hh信号传导。SuFu活性和稳定性的调节是控制Hh信号传导的关键。在这里，我们揭示了SuFu否定蛋白1（SNEP 1）作为一种新的Hh靶点，它增强了SuFu的泛素化和蛋白酶体降解，从而促进了Hh信号传导。我们进一步表明，E3泛素连接酶LNX1在SNEP1介导的SuFu降解中起着关键作用。因此，SNEP 1促进结直肠癌（CRC）细胞增殖和肿瘤生长。在CRC组织中检测到高水平的SNEP 1，并且与CRC患者的不良预后密切相关。此外，SNEP 1过表达降低了CRC细胞对抗Hh抑制剂的敏感性。总之，我们的研究结果表明，SNEP 1作为一种新的反馈调节Hh信号不稳定的SuFu和促进肿瘤生长和抗Hh耐药。
Hedgehog (Hh) signaling plays a critical role in embryogenesis and tissue homeostasis, and its deregulation has been associated with tumor growth. The tumor suppressor SuFu inhibits Hh signaling by preventing the nuclear translocation of Gli and suppressing cell proliferation. Regulation of SuFu activity and stability is key to controlling Hh signaling. Here, we unveil SuFu Negating Protein 1 (SNEP1) as a novel Hh target, that enhances the ubiquitination and proteasomal degradation of SuFu and thus promotes Hh signaling. We further show that the E3 ubiquitin ligase LNX1 plays a critical role in the SNEP1-mediated degradation of SuFu. Accordingly, SNEP1 promotes colorectal cancer (CRC) cell proliferation and tumor growth. High levels of SNEP1 are detected in CRC tissues and are well correlated with poor prognosis in CRC patients. Moreover, SNEP1 overexpression reduces sensitivity to anti-Hh inhibitor in CRC cells. Altogether, our findings demonstrate that SNEP1 acts as a novel feedback regulator of Hh signaling by destabilizing SuFu and promoting tumor growth and anti-Hh resistance.
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Sufu在肌型小鼠模型中发现的组织发育中的差异需求。
影响因子：
2.7
作者：
Hoelzl MA;Heby-Henricson K;Gerling M;Dias JM;Kuiper RV;Trünkle C;Bergström Å;Ericson J;Toftgård R;Teglund S
通讯作者：
Teglund S
DOI：
10.15252/embj.201593374
发表时间：
2016-07-01
期刊：
The EMBO journal
影响因子：
--
作者：
Raducu M;Fung E;Serres S;Infante P;Barberis A;Fischer R;Bristow C;Thézénas ML;Finta C;Christianson JC;Buffa FM;Kessler BM;Sibson NR;Di Marcotullio L;Toftgård R;D'Angiolella V
通讯作者：
D'Angiolella V
影响因子：
11.5
作者：
Kaye, Stanley B.;Fehrenbacher, Louis;Reddy, Josina C.
通讯作者：
Reddy, Josina C.
影响因子：
10.9
作者：
Schulman, Joshua M.;Oh, Dennis H.;Cho, Raymond J.
通讯作者：
Cho, Raymond J.
影响因子：
4.8
作者：
Chen, Yan;Yue, Shen;Cheng, Steven Y.
通讯作者：
Cheng, Steven Y.