Suppression of CUGBP1 inhibits growth of hepatocellular carcinoma cells

Liu, Yong; Huang, Hai; Yuan, Bo; Luo, Tianping; Li, Jianchao; Qin, Xihu

doi:10.25011/cim.v37i1.20864

Cited by 18 publications

(17 citation statements)

References 30 publications

(33 reference statements)

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“…In agreement with this prediction, CUGBP1-dependent accumulation of C/EBP␤-HDAC1 complexes leads to the repression of tumor suppressors p53, p21, and C/EBP␣ (15,16). Since previous studies reported the elevation of CUGBP1 in HCC from adult patients (28,29) and showed oncogenic activities of CUGBP1, we expected that liver cancer was inhibited in S302A mice. However, we found that S302A mice have more severe liver cancer under DEN-mediated carcinogenesis.…”

Section: Discussionsupporting

confidence: 61%

“…These studies have identified a new function of CUGBP1, which is the regulation of body homeostasis. Several previous reports found that CUGBP1 is elevated in patients with HCC and in mouse liver cancer mediated by DEN (15,28,29). In addition, a recent report showed that CUGBP1 is involved in the development of liver fibrosis, which is one of the critical steps of the development of liver cancer in humans (30).…”

Section: Discussionmentioning

confidence: 99%

“…Using tissue culture systems and Gank LKO mice, we found that Gank interacts with the S302A-CUGBP1 mutant and causes ubiquitination and subsequent degradation of CUGBP1 in the liver during development of liver cancer. Previous studies and our recent work showed that Gank is elevated in all types of liver cancer (20)(21)(22)(23)(24)(26)(27)(28)(29)(30)(31)(32)(33)(34), suggesting that this is the main mechanism that causes degradation of CUGBP1. Our results show that the Gankdependent ubiquitination of CUGBP1 is mainly observed in cytoplasm; however, CUGBP1 is mainly reduced in the nucleus.…”

Section: Discussionmentioning

confidence: 99%

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RNA Binding Protein CUGBP1 Inhibits Liver Cancer in a Phosphorylation-Dependent Manner

Lewis

Valanejad

Cast

et al. 2017

Molecular and Cellular Biology

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Despite intensive investigations, mechanisms of liver cancer are not known. Here, we identified an important step of liver cancer, which is the neutralization of tumor suppressor activities of an RNA binding protein, CUGBP1. The translational activity of CUGBP1 is activated by dephosphorylation at Ser302. We generated CUGBP1-S302A knock-in mice and found that the reduction of translational activity of CUGBP1 causes development of a fatty liver phenotype in young S302A mice. Examination of liver cancer in diethylnitrosamine (DEN)-treated CUGBP1-S302A mice showed these mice develop much more severe liver cancer that is associated with elimination of the mutant CUGBP1. Searching for mechanisms of this elimination, we found that the oncoprotein gankyrin (Gank) preferentially binds to and triggers degradation of dephosphorylated CUGBP1 (de-ph-S302-CUGBP1) or S302A mutant CUGBP1. To test the role of Gank in degradation of CUGBP1, we generated mice with liver-specific deletion of Gank. In these mice, the tumor suppressor isoform of CUGBP1 is protected from Gank-mediated degradation. Consistent with reduction of CUGBP1 in animal models, CUGBP1 is reduced in patients with pediatric liver cancer. Thus, this work presents evidence that de-ph-S302-CUGBP1 is a tumor suppressor protein and that the Gank-UPS-mediated reduction of CUGBP1 is a key event in the development of liver cancer. KEYWORDS CUGBP1, HCC, HBL, gankyrin, C/EBP␤, phosphorylation, C/EBP Q uiescent livers express up to 20 tumor suppressor proteins (1); however, they are eliminated by different mechanisms under conditions of liver cancer. Liver cancer remains the fifth most common cancer and the third most common cause of cancerrelated death in the world (2). The mechanisms of cancer-related elimination or reduction of tumor suppressor proteins include transcriptional repression of the genes, degradation of proteins, and posttranslational modifications that change biological activities of these proteins (1, 3, 4). A number of recent papers showed that certain proteins work as oncoproteins and as tumor suppressors depending on cell environment, target genes, and posttranslational modifications (5-12). In this regard, Dreijerink et al. have recently shown that menin tumor suppressor protein displays its tumor suppression activity in a variety of cancer cells; however, it possesses oncogenic activities in breast tumorigenesis (5). Another recent report revealed that the Kruppelassociated box zinc finger protein ZNF224 can behave as an oncoprotein and as a tumor suppressor protein and that these opposite activities of ZNF224 are controlled by specific protein-protein interactions (6). In addition to the opposite changes of the activities of tumor suppressor proteins and oncogenes, certain microRNAs display cell type-specific oncogenic or tumor suppression activities. Hickey et al. recently demon-

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Section: Discussionsupporting

confidence: 61%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

RNA Binding Protein CUGBP1 Inhibits Liver Cancer in a Phosphorylation-Dependent Manner

Lewis

Valanejad

Cast

et al. 2017

Molecular and Cellular Biology

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“…Timchenko et al 28. found that CUGBP1 expression was increased in the liver of older individuals and Liu et al 29. recently reported that the suppression of CUGBP1 inhibits the growth of hepatocellular carcinoma cells.…”

Section: Discussionmentioning

confidence: 99%

CUG-binding protein 1 regulates HSC activation and liver fibrogenesis

et al. 2016

Nat Commun

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Excessive activation of hepatic stellate cells (HSCs) is a key step in liver fibrogenesis. Here we report that CUG-binding protein 1 (CUGBP1) expression is elevated in HSCs and positively correlates with liver fibrosis severity in human liver biopsies. Transforming growth factor-beta (TGF-β) selectively increases CUGBP1 expression in cultured HSCs in a p38 mitogen-activated protein kinase (MAPK)-dependent manner. Knockdown of CUGBP1 inhibits alpha smooth muscle actin (α-SMA) expression and promotes interferon gamma (IFN-γ) production in HSCs in vitro. We further show that CUGBP1 specifically binds to the 3′ untranslated region (UTR) of human IFN-γ mRNA and promotes its decay. In mice, knockdown of CUGBP1 alleviates, whereas its overexpression exacerbates, bile duct ligation (BDL)-induced hepatic fibrosis. Therefore, CUGBP1-mediated IFN-γ mRNA decay is a key event for profibrotic TGF-β-dependent activation of HSCs, and inhibiting CUGBP1 to promote IFN-γ signalling in activated HSCs could be a novel strategy to treat liver fibrosis.

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“…Although CELF1 is best known for its role in the pathogenesis of Type 1 Myotonic Dystrophy19, it has been previously shown to play a protective role in chemotherapy-induced apoptosis49505152 and was identified as a top driver of colorectal tumourigenesis in an unbiased mutagenesis study53. However, none of these studies have delved into the mechanism by which CELF1 effects these various phenotypes.…”

Section: Discussionmentioning

confidence: 99%

CELF1 is a central node in post-transcriptional regulatory programmes underlying EMT

et al. 2016

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The importance of translational regulation in tumour biology is increasingly appreciated. Here, we leverage polyribosomal profiling to prospectively define translational regulatory programs underlying epithelial-to-mesenchymal transition (EMT) in breast epithelial cells. We identify a group of ten translationally regulated drivers of EMT sharing a common GU-rich cis-element within the 3′-untranslated region (3′-UTR) of their mRNA. These cis-elements, necessary for the regulatory activity imparted by these 3′-UTRs, are directly bound by the CELF1 protein, which itself is regulated post-translationally during the EMT program. CELF1 is necessary and sufficient for both mesenchymal transition and metastatic colonization, and CELF1 protein, but not mRNA, is significantly overexpressed in human breast cancer tissues. Our data present an 11-component genetic pathway, invisible to transcriptional profiling approaches, in which the CELF1 protein functions as a central node controlling translational activation of genes driving EMT and ultimately tumour progression.

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Suppression of CUGBP1 inhibits growth of hepatocellular carcinoma cells

Cited by 18 publications

References 30 publications

RNA Binding Protein CUGBP1 Inhibits Liver Cancer in a Phosphorylation-Dependent Manner

RNA Binding Protein CUGBP1 Inhibits Liver Cancer in a Phosphorylation-Dependent Manner

CUG-binding protein 1 regulates HSC activation and liver fibrogenesis

CELF1 is a central node in post-transcriptional regulatory programmes underlying EMT

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