RHBDD1 promotes colorectal cancer metastasis through the Wnt signaling pathway and its downstream target ZEB1

Zhang, Mengmeng; Miao, Fei; Huang, R. Stephanie; Liu, Wenjie; Zhao, Yuechao; Jiao, Tao; Lu, Yalan; Wu, Fan; Wang, Xiaojuan; Wang, Han; Zhao, Hong; Ju, Hongge; Miao, Shiying; Wang, Linfang; Song, Wei

doi:10.1186/s13046-018-0687-5

Cited by 68 publications

(53 citation statements)

References 39 publications

(61 reference statements)

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“…β-Catenin is one of the core proteins in the Wnt signaling pathway, and it was shown that phosphorylation at Ser552 and Ser675 of β-catenin could activate the β-catenin mediated signaling pathway. [24][25][26] In this study, in EYA4 overexpressed cells and EYA4 KO cells, the total level of β-catenin and p675-β-catenin did not change, but the level of p552-β-catenin was decreased in EYA4 overexpressed cells and increased in EYA4 KO cells. To investigate whether p552-β-catenin can facilitate transcription of MYCBP, we established β-catenin overexpressed plasmids with (WT) or without S552A mutation, a negative phosphorylated mutation of β-catenin at Ser552.…”

Section: Discussionmentioning

confidence: 49%

EYA4 inhibits hepatocellular carcinoma by repressing MYCBP by dephosphorylating β‐catenin at Ser552

Zhu

Cai

et al. 2019

Cancer Science

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Hepatocellular carcinoma (HCC) is one of the most common malignancies and the fourth leading cause of cancer‐related death worldwide. Our previous study showed that EYA4 functioned by suppressing growth of HCC tumor cells, but its molecular mechanism is still not elucidated. Based on the results of gene microassay, EYA4 was inversely correlated with MYCBP and was verified in human HCC tissues by immunohistochemistry and western blot. Overexpressed and KO EYA4 in human HCC cell lines confirmed the negative correlation between EYA4 and MYCBP by qRT‐PCR and western blot. Transfected siRNA of MYCBP in EYA4 overexpressed cells and overexpressed MYCBP in EYA4 KO cells could efficiently rescue the proliferation and G2/M arrest effects of EYA4 on HCC cells. Mechanistically, armed with serine/threonine‐specific protein phosphatase activity, EYA4 reduced nuclear translocation of β‐catenin by dephosphorylating β‐catenin at Ser552, thereby suppressing the transcription of MYCBP which was induced by β‐catenin/LEF1 binding to the promoter of MYCBP. Clinically, HCC patients with highly expressed EYA4 and poorly expressed MYCBP had significantly longer disease‐free survival and overall survival than HCC patients with poorly expressed EYA4 and highly expressed MYCBP. In conclusion, EYA4 suppressed HCC tumor cell growth by repressing MYCBP by dephosphorylating β‐catenin S552. EYA4 combined with MYCBP could be potential prognostic biomarkers in HCC.

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Section: Discussionmentioning

confidence: 49%

EYA4 inhibits hepatocellular carcinoma by repressing MYCBP by dephosphorylating β‐catenin at Ser552

Zhu

Cai

et al. 2019

Cancer Science

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“…Previous studies have reported that Capn4 promotes the invasion and metastasis of many cancers by activating the Wnt/β‐catenin signaling pathway . Many studies have also shown that ZEB1 is a downstream target of the Wnt/β‐catenin signaling pathway . Thus, we speculated that Capn4 regulates ZEB1 expression by activating the Wnt/β‐catenin signaling pathway in ESCC cells.…”

Section: Resultsmentioning

confidence: 83%

Capn4 promotes esophageal squamous cell carcinoma metastasis by regulating ZEB1 through the Wnt/β‐catenin signaling pathway

Zhao

et al. 2018

Thoracic Cancer

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BackgroundCapn4 and ZEB1 play important roles in the metastasis of several types of cancer. However, the roles and relationship of Capn4 and ZEB1 in esophageal squamous cell carcinoma (ESCC) remain unclear.MethodsESCC tumor tissues and corresponding normal esophageal epithelial tissues were obtained from 86 patients undergoing resection surgery at the Department of General Surgery, First Affiliated Hospital of Chinese PLA General Hospital from 2012 to 2017. Cell migration and invasion were examined via quantitative real‐time PCR and Western blot assay.ResultsOur results indicate that both Capn4 and ZEB1 are significantly upregulated in ESCC tissues compared to corresponding adjacent tissues, and a positive correlation between expression and associated malignant characteristics was found. Silencing of Capn4 expression markedly inhibited ESCC invasion and metastasis in vitro and in vivo, and was accompanied by decreased ZEB1 expression. Furthermore, the anti‐metastasis role of Capn4 silencing was reversed by ZEB1 overexpression, whereas knockdown of ZEB1 decreased ESCC metastasis driven by the upregulation of Capn4. Mechanistically, Capn4 regulated ZEB1 expression via activation of the Wnt/β‐catenin signaling pathway in ESCC cells.ConclusionOverall, our results show that enhanced Capn4 expression activates the Wnt/β‐catenin signaling pathway, resulting in increased ZEB1 expression and the promotion of ESCC cell metastasis.

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“…However, while GDNF is mutated in the signaling cascade, it may cause the pathway to be inactive. CARM1 (modified by methylation and phosphorylation) transmits the signal to TF ZEB1, which may be upregulated to cause cell proliferation Zhang et al, 2018). TF ZEB1 plays an important role in this pathway to connect the early-stage and mid-stage of CRC.…”

Section: Genetic and Epigenetic Progression Mechanisms Of Early-stagementioning

confidence: 99%

Investigation of the Genome-Wide Genetic and Epigenetic Networks for Drug Discovery Based on Systems Biology Approaches in Colorectal Cancer

Yeh

Chen

2020

Front. Genet.

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Colorectal cancer (CRC) is the third most commonly diagnosed type of cancer worldwide. The mechanisms leading to the progression of CRC are involved in both genetic and epigenetic regulations. In this study, we applied systems biology methods to identify potential biomarkers and conduct drug discovery in a computational approach. Using big database mining, we constructed a candidate protein-protein interaction network and a candidate gene regulatory network, combining them into a genome-wide genetic and epigenetic network (GWGEN). With the assistance of system identification and model selection approaches, we obtain real GWGENs for early-stage, mid-stage, and late-stage CRC. Subsequently, we extracted core GWGENs for each stage of CRC from their real GWGENs through a principal network projection method, and projected them to the Kyoto Encyclopedia of Genes and Genomes pathways for further analysis. Finally, we compared these core pathways resulting in different molecular mechanisms in each stage of CRC and identified carcinogenic biomarkers for the design of multiple-molecule drugs to prevent the progression of CRC. Based on the identified gene expression signatures, we suggested potential compounds combined with known CRC drugs to prevent the progression of CRC with querying Connectivity Map (CMap).

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RHBDD1 promotes colorectal cancer metastasis through the Wnt signaling pathway and its downstream target ZEB1

Cited by 68 publications

References 39 publications

EYA4 inhibits hepatocellular carcinoma by repressing MYCBP by dephosphorylating β‐catenin at Ser552

EYA4 inhibits hepatocellular carcinoma by repressing MYCBP by dephosphorylating β‐catenin at Ser552

Capn4 promotes esophageal squamous cell carcinoma metastasis by regulating ZEB1 through the Wnt/β‐catenin signaling pathway

Investigation of the Genome-Wide Genetic and Epigenetic Networks for Drug Discovery Based on Systems Biology Approaches in Colorectal Cancer

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