title: The CUL4B/AKT/β-Catenin Axis Restricts the Accumulation of Myeloid-Derived Suppressor Cells to Prohibit the Establishment of a Tumor-Permissive Microenvironment.
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.
authors.affiliation: Key Laboratory of Experimental Teratology, Ministry of Education/Institute of Molecular Medicine and Genetics, Shandong University School of Medicine, Jinan, China.
authors.forename: Yanyan
authors.initials: Y
authors.lastname: Qian
authors.affiliation: Key Laboratory of Experimental Teratology, Ministry of Education/Institute of Molecular Medicine and Genetics, Shandong University School of Medicine, Jinan, China.
authors.forename: Jupeng
authors.initials: J
authors.lastname: Yuan
authors.affiliation: Key Laboratory of Experimental Teratology, Ministry of Education/Institute of Molecular Medicine and Genetics, Shandong University School of Medicine, Jinan, China.
authors.forename: Huili
authors.initials: H
authors.lastname: Hu
authors.affiliation: Department of Breast Surgery, Qilu Hospital, Shandong University, Jinan, China.
authors.forename: Qifeng
authors.initials: Q
authors.lastname: Yang
authors.affiliation: Department of Medical Oncology, Cancer Center, Qilu Hospital, Shandong University, Jinan, China.
authors.forename: Jisheng
authors.initials: J
authors.lastname: Li
authors.affiliation: Key Laboratory of Experimental Teratology, Ministry of Education/Institute of Molecular Medicine and Genetics, Shandong University School of Medicine, Jinan, China.
authors.forename: Shuqian
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Experimental Teratology, Ministry of Education/Institute of Molecular Medicine and Genetics, Shandong University School of Medicine, Jinan, China.
authors.forename: Baichun
authors.initials: B
authors.lastname: Jiang
authors.affiliation: Key Laboratory of Experimental Teratology, Ministry of Education/Institute of Molecular Medicine and Genetics, Shandong University School of Medicine, Jinan, China. yxg8@sdu.edu.cn changshun.shao@gmail.com.
authors.forename: Changshun
authors.initials: C
authors.lastname: Shao
authors.affiliation: Key Laboratory of Experimental Teratology, Ministry of Education/Institute of Molecular Medicine and Genetics, Shandong University School of Medicine, Jinan, China. yxg8@sdu.edu.cn changshun.shao@gmail.com.
authors.forename: Yaoqin
authors.initials: Y
authors.lastname: Gong
mesh_terms: D000818:Animals; D016022:Case-Control Studies; D044842:Cullin Proteins / Q000378:metabolism*; D015536:Down-Regulation; D005260:Female; D006801:Humans; D008325:Mammary Neoplasms, Experimental / Q000378:metabolism* / Q000473:pathology; D008546:Melanoma, Experimental / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008875:Middle Aged; D022423:Myeloid Cells / Q000378:metabolism / Q000473:pathology; D009369:Neoplasms / Q000097:blood / Q000473:pathology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D000067996:RAW 264.7 Cells; D059016:Tumor Microenvironment / Q000502:physiology; D051176:beta Catenin / Q000378:metabolism*
chemical_list: C495267:CTNNB1 protein, mouse; C524851:Cul4B protein, mouse; D044842:Cullin Proteins; D051176:beta Catenin; D051057:Proto-Oncogene Proteins c-akt