CUL4B activates Wnt/β‐catenin signalling in hepatocellular carcinoma by repressing Wnt antagonists

Yuan, Jupeng; Han, Bo; Hu, Huili; Qian, Yanyan; Liu, Zhaojian; Zhao, Wei; Liang, Xiaohong; Jiang, Baichun; Shao, Changshun; Gong, Yaoqin

doi:10.1002/path.4492

Cited by 62 publications

(73 citation statements)

References 46 publications

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“…Wnt/β-catenin signaling pathway has been demonstrated abnormal activated in many kinds of cancer [55–57]. At present, Yuan et al [19] found CUL4B functioned as a positively regulator in Wnt/β-catenin signaling in HCC. CUL4B and β-catenin are over-expressed in HCC tissues and have positive correlation.…”

Section: Cul4b Related Signaling Pathwaysmentioning

confidence: 99%

The role of cullin4B in human cancers

Liu

Wang

2017

Exp Hematol Oncol

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Cullin 4B (CUL4B) is a scaffold of the Cullin4B-Ring E3 ligase complex (CRL4B) that plays an important role in proteolysis and is implicated in tumorigenesis. Aberrant expression of CUL4B has been reported in various types of human diseases. Recently, studies have shown that CUL4B was overexpressed in a multitude of solid neoplasms and affect the expression of several tumor suppressor genes. In this review, we aim to summarize the biological function of CUL4B in order to better understand its pathogenesis in human cancers.

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Section: Cul4b Related Signaling Pathwaysmentioning

confidence: 99%

The role of cullin4B in human cancers

Liu

Wang

2017

Exp Hematol Oncol

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“…CUL4B has recently been shown to be highly expressed in a variety of human malignancy and is positively correlated with tumor progression (25,26,29,39,40). In the current study, we demonstrated that CUL4B functions to limit the expansion and activity of MDSCs that are an integral part of the immunosuppressive tumor microenvironment.…”

Section: Discussionmentioning

confidence: 57%

“…Our recent study showed that CUL4B could activate Wnt/b-catenin signaling in human hepatocellular carcinoma (29). Thus, we next examined the effect of Cul4b ablation on the level of b-catenin in MDSCs.…”

Section: Aberrant Accumulation Of Mdscs Was Mediated By Downregulatiomentioning

confidence: 99%

“…Lentivirus shCul4b, PLOC-CUL4B, PLOC-CA-b-catenin, shPhlpp2, and shPpp2cb as well as their controls were prepared in HEK293T cells, as described previously (29). For the differentiation assay of mouse MDSCs and Lin À cells, 24 hours after infected with viral particles, the cells were cultured in fresh medium containing GM-CSF or GM-CSF and IL4 for 5 days.…”

Section: Lentiviral Plasmid Viral Production and Infectionmentioning

confidence: 99%

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The CUL4B/AKT/β-Catenin Axis Restricts the Accumulation of Myeloid-Derived Suppressor Cells to Prohibit the Establishment of a Tumor-Permissive Microenvironment

Qian

Yuan

et al. 2015

Cancer Research

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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/b-catenin pathway. Moreover, CUL4B repressed the phosphatases PP2A and PHLPP1/2 that dephosphorylate and inactivate AKT to sustain pathway activation. Importantly, the CUL4B/AKT/b-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 proand 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.Ó2015 AACR.

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“…Up to half of HCC patients have activation of Wnt/β-catenin signaling pathway [31,32,33]. When Wnt signaling is suppressed, generally due to a combination of lack of Wnt ligands and a prevalence of Wnt antagonists, β-catenin is sequentially phosphorylated by CK1 and GSK3β [34].…”

Section: Wnt/β-catenin Signaling and Epigeneticsmentioning

confidence: 99%

Epigenetic Activation of Wnt/β-Catenin Signaling in NAFLD-Associated Hepatocarcinogenesis

Tian

Mok

Yang

et al. 2016

Cancers

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Non-alcoholic fatty liver disease (NAFLD), characterized by fat accumulation in liver, is closely associated with central obesity, over-nutrition and other features of metabolic syndrome, which elevate the risk of developing hepatocellular carcinoma (HCC). The Wnt/β-catenin signaling pathway plays a significant role in the physiology and pathology of liver. Up to half of HCC patients have activation of Wnt/β-catenin signaling. However, the mutation frequencies of CTNNB1 (encoding β-catenin protein) or other antagonists targeting Wnt/β-catenin signaling are low in HCC patients, suggesting that genetic mutations are not the major factor driving abnormal β-catenin activities in HCC. Emerging evidence has demonstrated that obesity-induced metabolic pathways can deregulate chromatin modifiers such as histone deacetylase 8 to trigger undesired global epigenetic changes, thereby modifying gene expression program which contributes to oncogenic signaling. This review focuses on the aberrant epigenetic activation of Wnt/β-catenin in the development of NAFLD-associated HCC. A deeper understanding of the molecular mechanisms underlying such deregulation may shed light on the identification of novel druggable epigenetic targets for the prevention and/or treatment of HCC in obese and diabetic patients.

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CUL4B activates Wnt/β‐catenin signalling in hepatocellular carcinoma by repressing Wnt antagonists

Cited by 62 publications

References 46 publications

The role of cullin4B in human cancers

The role of cullin4B in human cancers

The CUL4B/AKT/β-Catenin Axis Restricts the Accumulation of Myeloid-Derived Suppressor Cells to Prohibit the Establishment of a Tumor-Permissive Microenvironment

Epigenetic Activation of Wnt/β-Catenin Signaling in NAFLD-Associated Hepatocarcinogenesis

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