DNA Methylation Profiling Identifies EYA4 Gene as a Prognostic Molecular Marker in Hepatocellular Carcinoma

Xu, Hongguo; Peng, Jianxin; Hao, Xiao-Yi; Cai, Jinhua; Liu, Liang; Zhai, Jingming; Zhang, Kunsong; Lai, Jiaming; Yin, Xiaoyu

doi:10.1245/s10434-013-3401-z

Cited by 28 publications

(30 citation statements)

References 34 publications

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“…Thus, we sought to study its role in ESCC. Numerous studies have indicated that EYA4 is aberrantly expressed in a variety of cancers, such as hepatocellular carcinoma, intrahepatic cholangio‐carcinoma, colorectal cancer and acute lymphoblastic leukemia . Consistent with these findings, in the present study, we found that EYA4 was aberrantly hypermethylated in both ESCC specimens and cell lines.…”

Section: Discussionsupporting

confidence: 91%

“…Numerous studies have indicated that EYA4 is aberrantly expressed in a variety of cancers, such as hepatocellular carcinoma, intrahepatic cholangio-carcinoma, colorectal cancer and acute lymphoblastic leukemia. 16,[19][20][21][22] Consistent with these findings, in the present study, we found that EYA4 was aberrantly hypermethylated in both ESCC specimens and cell lines. Then, we assessed the expression of EYA4 in ESCC cell lines and found that reduced EYA4 expression in 6 of 7 ESCC cell lines was associated with methylation status.…”

Section: Discussionsupporting

confidence: 91%

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Aberrant methylation of EYA4 promotes epithelial‐mesenchymal transition in esophageal squamous cell carcinoma

Luo

Shi

et al. 2018

Cancer Science

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EYA4, one of the four members of the EYA gene family, is associated with several human cancers. However, its biological functions and molecular mechanisms in the progression of cancer, particularly in esophageal squamous cell carcinoma (ESCC), remain unknown. In the present study, we found that EYA4 was underexpressed and hypermethylated in most of the ESCC cell lines tested (85.7%, 6/7). Treatment with 5‐aza‐dC and/or trichostatin A (TSA) restored EYA4 expression in ESCC cell lines, which indicates that EYA4 expression was epigenetically regulated. Similarly, EYA4 was aberrantly hypermethylated in ESCC tissues (78%, 39/50) and downregulation of EYA4 occurred in approximately 65% of primary ESCC at protein level where it was associated significantly with TNM stage and lymph node metastases. Knockdown of EYA4 in KYSE30 and KYSE70 ESCC cells using small hairpin RNA increased migration and invasive motility in vitro. Conversely, the overexpression of EYA4 in KYSE180 and KYSE450 promoted an epithelial phenotype, which consisted of decreased migration and invasion abilities and a decrease in TGF‐β1‐induced epithelial‐mesenchymal transition. Mechanistically, EYA4 overexpression reduced the phosphorylation of Akt and glycogen synthase kinase (GSK) 3β, which led to the inactivation of slug. In addition, we found that TGF‐β1 decreased EYA4 expression in both a dose‐dependent and a time‐dependent manner in KYSE30 cells, accompanied by an increase in the expression of DNA methyltransferases, especially DNMT3A. In summary, EYA4 is frequently hypermethylated in ESCC and may function as a tumor suppressor gene in the development of ESCC.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionsupporting

confidence: 91%

Aberrant methylation of EYA4 promotes epithelial‐mesenchymal transition in esophageal squamous cell carcinoma

Luo

Shi

et al. 2018

Cancer Science

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“…; *, p<0.05. Cellular Physiology and Biochemistry Cellular Physiology and Biochemistry one of the EYA family members, has been reported to play an important role in various cancers [11,12,33,34]. In this study, we found that EYA4 was upregulated in glioma and its levels were positively correlated with advanced tumor stage, which was consistent with its previously reported roles in other cancers.…”

Section: Discussionsupporting

confidence: 91%

EYA4 Promotes Cell Proliferation Through Downregulation of p27Kip1 in Glioma

Qiu

Xia³

et al. 2018

Cell Physiol Biochem

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Background/Aims: Accumulating evidence suggests that Eyes Absent Homologue 4 (EYA4) plays an important role in tumorigenesis and progression of various cancers. However, the role of EYA4 in glioma development is still unclear. Methods: The expression of EYA4 was examined in glioma tissues by immunohistochemistry. Cell viability and apoptosis were analyzed by CCK-8, BrdU assay, and flow cytometry. Results: We found that EYA4 was upregulated in glioma, and its expression was positively correlated with advanced tumor stage. Moreover, higher expression of EYA4 predicted a worse overall survival in patients with glioma. Forced overexpression of EYA4 enhanced glioma cell proliferation, and EYA4 suppressed the expression of p27Kip1 directly in these cells. Furthermore, Six1 was required for EYA4 to suppress the expression of p27Kip1 in glioma. Conclusion: Together, we demonstrate that EYA4 promotes cell proliferation by directly suppressing the expression of p27Kip1 in glioma.

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“…Indeed, EYA4 protein levels were lower in CCA patients with lymph node metastasis, and low expression of EYA4 was an independent prognostic factor for overall and disease-free survival 117 . Of note, EYA4 down-regulation in CCA tissue might result from gene promoter hypermethylation, as reported in other cancer types 118,119 . Although the precise antitumor function played by EYA4 in CCA requires further exploration, it is worth noting that in colorectal cancer, EYA4 keeps at bay the pro-neoplastic Wnt signaling by stimulating DKK1 expression 119 .…”

Section: Novel Signaling Mechanisms and Trascription Factors Promotinmentioning

confidence: 54%

Molecular Mechanisms Driving Cholangiocarcinoma Invasiveness: An Overview

et al. 2018

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The acquisition of invasive functions by tumor cells is a first and crucial step towards the development of metastasis, which nowadays represents the main cause of cancer-related death. Cholangiocarcinoma (CCA), a primary liver cancer originating from the biliary epithelium, typically develops intrahepatic or lymph node metastases at early stages, thus preventing the majority of patients from undergoing curative treatments, consistent with their very poor prognosis. As in most carcinomas, CCA cells gradually adopt a motile, mesenchymal-like phenotype, enabling them to cross the basement membrane, detach from the primary tumor, and invade the surrounding stroma. Unfortunately, little is known about the molecular mechanisms that synergistically orchestrate this pro-invasive phenotypic switch. Autocrine and paracrine signals (cyto/chemokines, growth factors, morphogens) permeating the tumor microenvironment undoubtedly play a prominent role in this context. Moreover, a number of recently identified signaling systems are currently drawing attention as putative mechanistic determinants of CCA cell invasion. They encompass transcription factors, protein kinases and phosphatases, ubiquitin ligases, adaptor proteins, and miRNAs, whose aberrant expression may result from either stochastic mutations or the abnormal activation of upstream pro-oncogenic pathways. Herein, we sought to summarize the most relevant molecules in this field, and to discuss their mechanism of action and potential prognostic relevance in CCA. Hopefully, a deeper knowledge of the molecular determinants of CCA invasiveness will help to identify clinically useful biomarkers and novel druggable targets, with the ultimate goal to develop innovative approaches to the management of this devastating malignancy.

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DNA Methylation Profiling Identifies EYA4 Gene as a Prognostic Molecular Marker in Hepatocellular Carcinoma

Abstract: EYA4 functions as a prognostic molecular marker in HCC. Its aberrant hypermethylation and subsequent down-regulation may promote tumor progression.

Cited by 28 publications

References 34 publications

Aberrant methylation of EYA4 promotes epithelial‐mesenchymal transition in esophageal squamous cell carcinoma

Aberrant methylation of EYA4 promotes epithelial‐mesenchymal transition in esophageal squamous cell carcinoma

EYA4 Promotes Cell Proliferation Through Downregulation of p27Kip1 in Glioma

Molecular Mechanisms Driving Cholangiocarcinoma Invasiveness: An Overview

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