EYA2 Correlates With Clinico-Pathological Features of Breast Cancer, Promotes Tumor Proliferation, and Predicts Poor Survival

Xu, Hanxiao; Jiao, Yanmei; Yi, Ming; Zhao, Wei; Wu, Zeyu

doi:10.3389/fonc.2019.00026

Cited by 21 publications

(16 citation statements)

References 47 publications

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“…This ligand-independent mechanism of ERß activation may be responsible for the tumor repressive effects of ERß in the absence of exogenous ligand, and when c-Abl/EYA2 ratios are high. It is also consistent with multiple reports associating high EYA2 levels with a worse prognosis in breast cancer (Farabaugh et al 2012;Xu et al 2019).…”

Section: Estrogen Receptor Erßsupporting

confidence: 92%

The multi-functional eyes absent proteins

Hegde

Roychoudhury

Pandey

2020

Critical Reviews in Biochemistry and Molecular Biology

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The Eyes Absent (EYA) proteins are the only known instance of a single polypeptide housing the following three separable biochemical activities: tyrosine phosphatase, threonine phosphatase, and transactivation. This uniquely positions the EYAs to participate in both transcriptional regulation and signal transduction pathways. But it also complicates the assignment of biological roles to individual biochemical activities through standard loss-of-function experiments. Nevertheless, there is an emerging literature linking developmental and pathological functions with the various EYA activities, and a growing list of disease states that might benefit from EYA-targeted therapeutics. There also remain multiple unresolved issues with significant implications for our understanding of how the EYAs might impact such ubiquitous signaling cascades as the MYC and Notch pathways. This review will describe the unique juxtaposition of biochemical activities in the EYAs, their interaction with signaling pathways and cellular processes, emerging evidence of roles in disease states, and the feasibility of therapeutic targeting of individual EYA activities. We will focus on the phosphatase activities of the vertebrate EYA proteins and will examine the current state of knowledge regarding:substrates and signaling pathways affected by the EYA tyrosine phosphatase activity; modes of regulation of the EYA tyrosine phosphatase activity; signaling pathways that implicate the threonine phosphatase activity of the EYAs including a potential interaction with PP2A-B55a; the interplay between the two phosphatase activities and the transactivation function of the EYAs; disease states associated with the EYAs and the current state of development of EYA-targeted therapeutics.

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Section: Estrogen Receptor Erßsupporting

confidence: 92%

The multi-functional eyes absent proteins

Hegde

Roychoudhury

Pandey

2020

Critical Reviews in Biochemistry and Molecular Biology

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“…In this report we used TCGA methylation data to analyze EYA2 methylation status of pan-cancer, in which we found EYA2 was hypermethylated in breast cancer than adjacent tissues. However, several studies reported that EYA2 promoted the progression of breast cancer [ 6 , 21 , 22 ]. This brings the complexity of cancer research, suggesting the methylation of EYA2 may not be the main cause modification of breast cancer progression to a great extent.…”

Section: Discussionmentioning

confidence: 99%

EYA2 suppresses the progression of hepatocellular carcinoma via SOCS3-mediated blockade of JAK/STAT signaling

Liu

Zhang

et al. 2021

Mol Cancer

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Background Somatic mutations are involved in hepatocellular carcinoma (HCC) progression, but the genetic mechanism associated to hepatocarcinogenesis remains poorly understood. We report that Eyes absent homolog 2 (EYA2) suppresses the HCC progression, while EYA2(A510E) mutation identified by exome sequencing attenuates the tumor-inhibiting effect of EYA2. Methods Whole-exome sequencing was performed on six pairs of human HCC primary tumors and matched adjacent tissues. Focusing on EYA2, expression level of EYA2 in human HCC samples was evaluated by quantitative real-time PCR, western blot and immunohistochemistry. Loss- and gain-of-function studies, hepatocyte-specific deletion of EYA2 (Eya2−/−) in mice and RNA sequencing analysis were used to explore the functional effect and mechanism of EYA2 on HCC cell growth and metastasis. EYA2 methylation status was evaluated using Sequenom MassARRAY and publicly available data analysis. Results A new somatic mutation p.Ala510Glu of EYA2 was identified in HCC tissues. The expression of EYA2 was down-regulated in HCC and associated with tumor size (P = 0.001), Barcelona Clinic Liver Cancer stage (P = 0.016) and tumor differentiation (P = 0.048). High level of EYA2 was correlated with a favorable prognosis in HCC patients (P = 0.003). Results from loss-of-function and gain-of-function experiments suggested that knockdown of EYA2 enhanced, while overexpression of EYA2 attenuated, the proliferation, clone formation, invasion, and migration of HCC cells in vitro. Delivery of EYA2 gene had a therapeutic effect on inhibition of orthotopic liver tumor in nude mice. However, EYA2(A510E) mutation led to protein degradation by unfolded protein response, thus weakening the inhibitory function of EYA2. Hepatocyte-specific deletion of EYA2 in mice dramatically promoted diethylnitrosamine-induced HCC development. EYA2 was also down-regulated in HCC by aberrant CpG methylation. Mechanically, EYA2 combined with DACH1 to transcriptionally regulate SOCS3 expression, thus suppressing the progression of HCC via SOCS3-mediated blockade of the JAK/STAT signaling pathway. Conclusions In our study, we identified and validated EYA2 as a tumor suppressor gene in HCC, providing a new insight into HCC pathogenesis.

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“…A n E d U a s s a y w a s c o n d u c t e d a c c o r d i n g t o t h e manufacturer's instructions (Cell-LightTM EdU Apollo 567 Kit, Catalog No: C10310-1, RIBOBIO) (9). Firstly, cells were seeded in 24-well plates at a density of 3×10 3 per well and incubated for 2 days.…”

Section: Edu Assaymentioning

confidence: 99%

Upregulation of STAT1-CCL5 axis is a biomarker of colon cancer and promotes the proliferation of colon cancer cells

Niu

Dong

et al. 2020

Ann Transl Med

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Background: Colorectal cancer (CRC) is the third most commonly diagnosed cancer in men and women globally. Investigating genetic ground differences between normal and CRC tissues would be significant for identifying some key oncogenic pathways and developing anti-cancer agents.Methods: Weighted gene co-expression network analysis (WGCNA) method was used to screen out core pathways related to the clinical traits of CRC patients. Then, multiple databases were utilized to further verify the hub genes obtained from data mining. Finally, to explore the role of hub genes in CRC, cell counting and EdU assays were performed. Results:The results of the WGCNA analysis showed that a module (turquoise module) was highly related with CRC differentiation grade (R =0.53, P<0.0001). Enrichment analysis indicated that genes of the turquoise module were remarkably enriched in multiple inflammatory processes and pathways. Among all hub genes of the turquoise module, the mRNA levels of STAT1 and CCL5 were significantly higher in CRC than in normal colon tissues. STAT1 expression was highly positively correlated with the level of CCL5. The results of the cell counting, EdU, CCK-8, and CFSE staining assays showed that interfering with STAT1 and CCL5 could inhibit the proliferation of CRC cells.Conclusions: Our study indicated that the STAT1-CCL5 axis is an important modulator in the development of CRC through promoting cell proliferation. Moreover, the levels of STAT1 and CCL5 might be valuable biomarkers for CRC screening.

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EYA2 Correlates With Clinico-Pathological Features of Breast Cancer, Promotes Tumor Proliferation, and Predicts Poor Survival

Cited by 21 publications

References 47 publications

The multi-functional eyes absent proteins

The multi-functional eyes absent proteins

EYA2 suppresses the progression of hepatocellular carcinoma via SOCS3-mediated blockade of JAK/STAT signaling

Upregulation of STAT1-CCL5 axis is a biomarker of colon cancer and promotes the proliferation of colon cancer cells

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