The CUL4B/AKT/β-Catenin Axis Restricts the Accumulation of Myeloid-Derived Suppressor Cells to Prohibit the Establishment of a Tumor-Permissive Microenvironment
PUBLISHED: 2015-12-29  873 total views, 1 today

Yanyan Qian1Jupeng Yuan1Huili Hu1Qifeng Yang2Jisheng Li3,Shuqian Zhang1Baichun Jiang1Changshun Shao1,*, and Yaoqin Gong1,*

Author Affiliations

1Key Laboratory of Experimental Teratology, Ministry of Education/Institute of Molecular Medicine and Genetics, Shandong University School of Medicine, Jinan, China.

2Department of Breast Surgery, Qilu Hospital, Shandong University, Jinan, China.                                                   

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.

Disclaimer: Only abstract of articles from non-members were published. This page aims to promote Chinese scientific research. There is no conflicts of interest with any journals reserved the copyright. For more please contact the author.


Author
Dr. Gong Yaoqin
+ Author Profile

Dr. Gong Yaoqin

Cheung Kong Scholar Chair Professor, Dean of the Shandong University School of Medicine.

Email: yxg8@sdu.edu.cn


Research Area

  • Mapping, cloning and functional analysis of neuromusculardisease gene

  • Mapping, cloning and functional analysis of bone andjoint disease gene

  • Analysis ofcardiovascular diseasesusceptibility gene

 

Research Project

  • Two X- linked mental retardation gene cloning

  • Research of related genes for bone and joint disease

  • Osteoporosis pseudoglioma syndrome gene cloning

 


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