Dysregulation of the miR-194-CUL4B negative feedback loop drives tumorigenesis in non-small-cell lung carcinoma.
Dysregulation of the miR-194-CUL4B negative feedback loop drives tumorigenesis in non-small-cell lung carcinoma.
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miR-194-CUL4B负反馈环的失调驱动非小细胞肺癌的肿瘤发生
DOI：
10.1002/1878-0261.12038
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发表时间：
2017-03
影响因子：
6.6
通讯作者：
Gong Y
中科院分区：
文献类型：
--
作者：
Mi J;Zou Y;Lin X;Lu J;Liu X;Zhao H;Ye X;Hu H;Jiang B;Han B;Shao C;Gong Y
Cullin 4 B（CUL 4 B）是一种组装CRL 4 B泛素连接酶复合物的支架蛋白，在许多类型的癌症中过表达，并通过表观遗传机制抑制许多肿瘤抑制因子。然而，CUL 4 B上调的机制仍有待阐明。在这里，我们发现CUL 4 B在非小细胞肺癌（NSCLC）组织中上调，并且是体外细胞增殖和迁移以及体内异种移植肿瘤形成所必需的。我们发现microRNA-194（miR-194）和CUL 4 B蛋白在癌症标本中呈负相关，并证明miR-194可以通过直接靶向其3′-UTR下调CUL 4 B。我们还发现，CUL 4 B可以通过miR-194依赖性方式被p53负调控。miR-194进一步显示通过下调CUL 4 B来减弱肺癌细胞的恶性表型。有趣的是，CRL 4 B也通过催化H2 AK 119的单泛素化和与PRC 2配位促进编码miR-194的基因簇H3 K27的三甲基化来表观遗传抑制miR-194。CRL 4 B复合物中的另一种成分RBX 1也是NSCLC细胞中miR-194的靶向。因此，我们的研究结果在miR-194和CRL 4 B之间建立了一个双负反馈环，其失调有助于肿瘤发生。miR-194作为CUL 4 B负调节因子的功能在肺癌中具有治疗意义。
Cullin 4B (CUL4B), a scaffold protein that assembles CRL4B ubiquitin ligase complexes, is overexpressed in many types of cancers and represses many tumor suppressors through epigenetic mechanisms. However, the mechanisms by which CUL4B is upregulated remain to be elucidated. Here, we show that CUL4B is upregulated in non‐small‐cell lung carcinoma (NSCLC) tissues and is critically required for cell proliferation and migration in vitro and for xenograft tumor formation in vivo. We found that microRNA‐194 (miR‐194) and CUL4B protein were inversely correlated in cancer specimens and demonstrated that miR‐194 could downregulate CUL4B by directly targeting its 3′‐UTR. We also showed that CUL4B could be negatively regulated by p53 in a miR‐194‐dependent manner. miR‐194 was further shown to attenuate the malignant phenotype of lung cancer cells by downregulating CUL4B. Interestingly, CRL4B also epigenetically represses miR‐194 by catalyzing monoubiquitination at H2AK119 and by coordinating with PRC2 to promote trimethylation at H3K27 at the gene clusters encoding miR‐194. RBX1, another component in CRL4B complex, is also targeted by miR‐194 in NSCLC cells. Our results thus establish a double‐negative feedback loop between miR‐194 and CRL4B, dysregulation of which contributes to tumorigenesis. The function of miR‐194 as a negative regulator of CUL4B has therapeutic implications in lung cancer.
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影响因子：
6.2
作者：
Hibino, S.;Saito, Y.;Muramatsu, T.;Otani, A.;Kasai, Y.;Kimura, M.;Saito, H.
通讯作者：
Saito, H.
影响因子：
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作者：
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通讯作者：
Fraser, Donald J.
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影响因子：
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作者：
Chen XY;Zhou J;Luo LP;Han B;Li F;Chen JY;Zhu YF;Chen W;Yu XP
通讯作者：
Yu XP
影响因子：
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作者：
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通讯作者：
Zhao, Guoqiang
影响因子：
4.7
作者：
Khella, H. W. Z.;Bakhet, M.;Yousef, G. M.
通讯作者：
Yousef, G. M.