Yanyan Qian¹, Jupeng Yuan¹, Huili Hu¹, Qifeng Yang², Jisheng Li³,Shuqian Zhang¹, Baichun Jiang¹, Changshun Shao^1,*, and Yaoqin Gong^1,*

Author Affiliations

3Department of Medical Oncology, Cancer Center, Qilu Hospital, Shandong University, Jinan, China.

Corresponding Authors:
Yaoqin Gong, Shandong University School of Medicine, Jinan, Shandong 250012, China. Phone: 86-531-8838-2115; Fax: 86-531-8838-2502; E-mail: yxg8@sdu.edu.cn; and Changshun Shao, changshun.shao@gmail.com

Abstract

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/β-catenin pathway. Moreover, CUL4B repressed the phosphatases PP2A and PHLPP1/2 that dephosphorylate and inactivate AKT to sustain pathway activation. Importantly, the CUL4B/AKT/β-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. Cancer Res; 75(23); 5070–83. ©2015 AACR.

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