ArhGAP30 promotes p53 acetylation and function in colorectal cancer

Wang, Jilin; Qian, Jin; Hu, Ye; Kong, Xuan; Chen, Haoyan; Shi, Qinghua; Jiang, Long; Wu, Chenming; Zou, Weiping; Chen, Yingxuan; Xu, Jie; Fang, Jing‐Yuan

doi:10.1038/ncomms5735

Cited by 61 publications

(63 citation statements)

References 56 publications

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“…111,112 In response to DNA damage, the p53 protein triggers multiple cellular responses, including cell cycle arrest, DNA repair and apoptosis, cellular differentiation, metabolism, angiogenesis and the immune response. [113][114][115] In the carcinogenic progression of GC, loss of the TP53 locus is one of the most common mechanisms involved in this gene dysfunction and is frequently found in GC. 87,88,90,116 A significant correlation has been found between loss of TP53 and gastric precancerous lesions, suggesting that TP53 CNV may be an early event in gastric carcinogenesis.…”

Section: Chromosomementioning

confidence: 99%

Gastric cancer and gene copy number variation: emerging cancer drivers for targeted therapy

2015

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Gastric cancer (GC) is among the most common malignancy in the world with poor prognosis and limited treatment options. It has been established that gastric carcinogenesis is caused by a complex interaction between host and environmental factors. Copy number variation (CNV) refers to a form of genomic structural variation that results in abnormal gene copy numbers, including gene amplification, gain, loss and deletion. DNA CNV is an important influential factor for the expression of both protein-coding and non-coding genes, affecting the activity of various signaling pathways. CNV arises as a result of preferential selection that favors cancer development, and thus, targeting the amplified 'driver genes' in GC may provide novel opportunities for personalized therapy. The detection of CNVs in chromosomal or mitochondrial DNA from tissue or blood samples may assist the diagnosis, prognosis and targeted therapy of GC. In this review, we discuss the recent CNV discoveries that shed light on the molecular pathogenesis of GC, with a specific emphasis on CNVs that display diagnostic, prognostic or therapeutic significances in GC.

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Section: Chromosomementioning

confidence: 99%

Gastric cancer and gene copy number variation: emerging cancer drivers for targeted therapy

2015

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“…Studies have revealed that low expression of the ArhGAP30 scaffold protein was associated with poor survival of colorectal cancer patients ( Fig. 3 ), which was supported by independent patient cohorts [44] . The prognostic significance of ArhGAP30 was independent of the American Joint Committee on Cancer (AJCC) tumor stage, suggesting that this biomarker may be used to complement traditional prognostic strategies.…”

Section: Prognostic Significance Of Scaffold Proteinsmentioning

confidence: 62%

“…TRB1 physically ties p53, exerts control over the HDAC1-dependent deacetylation of p53, and thereby suppresses the binding efficacy of the particular DNA and p53. Adapted from Xu et al [32] , Miyajima et al [34] , and Wang et al [44] .…”

Section: Scaffold Proteins That Regulate P53 Ubiquitinationmentioning

confidence: 99%

“…Experiments have indicated that tumor susceptibility and aggression may partly rely on the gene dose of IQGAP1 [47] , and the absence of IQGAP1 may predict a favorable prognosis [18] . Interestingly, treating tumor-bearing mice with the WW peptide, the only known conserved domain in IQGAP1 bound to ERK, can Adapted from Kong et al [3] and Wang et al [44] .…”

Section: Prognostic Significance Of Scaffold Proteinsmentioning

confidence: 99%

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Scaffold Proteins in Gastrointestinal Tumors as a Shortcut to Oncoprotein Activation

Wang

Yao

et al. 2017

Gastrointest Tumors

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Background: The development of cancer involves uncontrolled cell proliferation, and multiple signaling pathways that regulate cell proliferation have been found to be dysregulated in cancers. Extracellular signal-regulated protein kinase (ERK) is one of three major subtypes in the mitogen-activated protein kinase (MAPK) families. The MAPK/ERK pathway (RAS/RAF1/MEK/ERK) plays an important part in promoting cell proliferation in response to growth factors, thereby serving as a driving signal in gastrointestinal (GI) tumors. In contrast, the p53 tumor suppressor functions as a “guardian of the genome” and stops cell proliferation when oncogenic signaling is activated. Summary: Both pathways constrain each other in healthy GI epithelium, facilitating controlled proliferation that is essential for tissue repair and regeneration. However, in GI tumors, the MAPK/ERK and p53 pathways are commonly dysregulated, in part due to abnormal posttranslational modifications. Hyperphosphorylation of the ERK protein causes sustained activation of cell proliferation, whereas hypoacetylation of the p53 protein impairs its transcriptional function and blocks cell apoptosis. Multiple scaffold proteins have been found to regulate the posttranslational modifications of ERK and p53 proteins in GI tumors. Key Message: Abnormal expression of scaffold proteins may contribute to the dysregulation of the MAPK and p53 signaling pathways and thereby contribute to the development of GI tumors. Practical Implications: Scaffold proteins are potential biomarkers and therapeutic targets in GI tumors.

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“…RhoGAPs can also suppress cancer growth and invasion by RhoGAP-independent mechanisms, such as the p53 [25] and Wnt/β-catenin pathways [26]. Here, GSEA in TCGA dataset showed that ARHGAP17 expression was negatively correlated with the Wnt signaling pathway in colon cancer specimens.…”

Section: Discussionmentioning

confidence: 80%

Tumor Suppressive Role of ARHGAP17 in Colon Cancer Through Wnt/β-Catenin Signaling

Pan¹,

Deng²,

Fu³

et al. 2018

Cell Physiol Biochem

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Background/Aims: A few Rho GTPase activating proteins (RhoGAPs) have been identified as tumor suppressors in a variety of human cancers. ARHGAP17, a member of RhoGAPs, has been reported to be involved in the maintenance of tight junction and epithelial barrier. The present study aimed to explore its expression in colon cancer and the possible function in colonic carcinogenesis. Methods: The mRNA and protein expression was assessed by realtime PCR and immunoblotting, respectively. Cell Counting Kit-8 (CCK-8) and Transwell assays were performed to evaluate cell proliferation and invasion, respectively. Results: We found that ARHGAP17 expression was obviously lower in colon cancer specimens than in normal colonic mucosa. ARHGAP17 expression was associated with tumor stage, size and differentiation. In vitro analysis demonstrated that ARHGAP17 overexpression inhibited cell growth and invasion of HCT-8 and HCT-116 cells. In addition, an in vivo experimental metastasis model showed that ARHGAP17 overexpression restricted cancer metastasis to the lung. Mechanically, we found that Wnt signaling contributed to the functions of ARHGAP17 in colon cancer cells. Gene set enrichment analysis (GSEA) in The Cancer Genome Atlas dataset showed that the Wnt signaling pathway was negatively associated with ARHGAP17 expression. The mRNA expression of β-catenin (an important signaling transducer of canonical Wnt signaling) gene (CTNNB1) was negatively correlated with ARHGAP17 expression. Immunoblot analysis of downstream effectors of β-catenin (c-Myc/p27 and MMP7) in ARHGAP17 overexpressing colon cancer cells and metastatic tumors within the lung also validated the GSEA result. ARHGAP17 overexpression increased the phosphorylation of glycogen synthetase kinase 3β, and decreased β-catenin nuclear localization and transcriptional activity. Furthermore, inhibition of Wnt signaling by Wnt Inhibitor Factor-1 (WIF-1) in HIEC cells with ARHGAP17 knockdown significantly attenuated the promotion effects of ARHGAP17 knockdown on cell proliferation, invasion and the activation of β-catenin. Conclusion: these results suggest that ARHGAP17 might serve as a tumor suppressor in colon cancer progression and metastasis through Wnt/β-catenin signaling pathway.

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ArhGAP30 promotes p53 acetylation and function in colorectal cancer

Cited by 61 publications

References 56 publications

Gastric cancer and gene copy number variation: emerging cancer drivers for targeted therapy

Gastric cancer and gene copy number variation: emerging cancer drivers for targeted therapy

Scaffold Proteins in Gastrointestinal Tumors as a Shortcut to Oncoprotein Activation

Tumor Suppressive Role of ARHGAP17 in Colon Cancer Through Wnt/β-Catenin Signaling

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