The CUL4B/AKT/β-Catenin Axis Restricts the Accumulation of Myeloid-Derived Suppressor Cells to Prohibit the Establishment of a Tumor-Permissive Microenvironment
The CUL4B/AKT/β-Catenin Axis Restricts the Accumulation of Myeloid-Derived Suppressor Cells to Prohibit the Establishment of a Tumor-Permissive Microenvironment
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CUL4B/AKT/β-连环蛋白轴限制骨髓源性抑制细胞的积累，以阻止肿瘤生长微环境的建立。
DOI：
10.1158/0008-5472.can-15-0898
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发表时间：
2015-12-01
期刊：
影响因子：
11.2
通讯作者：
Gong, Yaoqin
中科院分区：
文献类型：
--
作者：
Qian, Yanyan;Yuan, Jupeng;Gong, Yaoqin
癌症进展需要一个宽松的微环境，使癌症免受宿主免疫监视。髓源性抑制细胞（MDSC）的存在是肿瘤容许微环境的关键特征。Cullin 4 B（CUL 4 B）是Cullin 4 B-RING E3连接酶复合物（CRL 4 B）中的支架蛋白，通过多种表观遗传机制抑制肿瘤抑制因子，并在许多恶性肿瘤中过表达。我们在这里报告，CUL 4 B出乎意料地在多种肿瘤环境中作为MDSC功能的负调节剂发挥作用。由Tek-Cre驱动的造血系统中CUL 4 B的条件性消融导致MDSC的积累和活性显著增强。从机制上讲，我们证明了在缺乏CUL 4 B的情况下MDSC的异常丰度是由AKT/β-连环蛋白途径的下调介导的。此外，CUL 4 B抑制磷酸酶PP 2A和PHLPP 1/2，其去磷酸化和抑制AKT以维持途径活化。重要的是，CUL 4 B/AKT/β-连环蛋白轴在健康个体的MDSC中下调，并在荷瘤小鼠和癌症患者中进一步受到抑制。因此，我们的研究结果指出了CUL 4 B在恶性肿瘤中的促肿瘤发生和抗肿瘤发生作用，其中其阻碍肿瘤支持微环境形成的能力可能是特定的。(C)2015年AACR。
Cancer progression requires a permissive microenvironment that shields cancer from the host immunosurveillance. The presence of myeloid-derived suppressor cells (MDSC) is a key feature of a tumor-permissive microenvironment. Cullin 4B (CUL4B), a scaffold protein in the Cullin 4B-RING E3 ligase complex (CRL4B), represses tumor suppressors through diverse epigenetic mechanisms and is overexpressed in many malignancies. We report here that CUL4B unexpectedly functions as a negative regulator of MDSC functions in multiple tumor settings. Conditional ablation of CUL4B in the hematopoietic system, driven by Tek-Cre, resulted in significantly enhanced accumulation and activity of MDSCs. Mechanistically, we demonstrate that the aberrant abundance of MDSCs in the absence of CUL4B was mediated by the downregulation of the AKT/beta-catenin pathway. Moreover, CUL4B repressed the phosphatases PP2A and PHLPP1/2 that dephosphorylate and inactivate AKT to sustain pathway activation. Importantly, the CUL4B/AKT/beta-catenin axis was downregulated in MDSCs of healthy individuals and was further suppressed in tumor-bearing mice and cancer patients. Thus, our findings point to a pro- and antitumorigenic role for CUL4B in malignancy, in which its ability to impede the formation of a tumor-supportive microenvironment may be context-specific. (C) 2015 AACR.