EYA4 Promotes Cell Proliferation Through Downregulation of p27Kip1 in Glioma

Li, Zhaoming; Qiu, Ran; Xia, Qi‐Dong; Tian, Tian

doi:10.1159/000493631

Cited by 17 publications

(6 citation statements)

References 32 publications

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“…Further investigation by live imaging and the FUCCI system demonstrated that cells silenced for EYA4 undergo slower DNA synthesis, halting cell cycle progression, and undergoing endoreplication as a result of missed mitosis initiation. Our data are in line with previous observations in glioma where EYA4 over-expression promotes cell proliferation by directly suppressing the expression of p27 KIP1 , suggesting p27 KIP1 as a transcriptional target of EYA4 [ 48 ].…”

Section: Discussionsupporting

confidence: 93%

EYA4 promotes breast cancer progression and metastasis through its role in replication stress avoidance

de la Peña Avalos,

Tropée,

Duijf

et al. 2023

Mol Cancer

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The Eyes Absent (EYA) family of proteins is an atypical group of four dual-functioning protein phosphatases (PP), which have been linked to many vital cellular processes and organogenesis pathways. The four family members of this PP family possess transcriptional activation and phosphatase functions, with serine/threonine and tyrosine phosphatase domains. EYA4 has been associated with several human cancers, with tumor-suppressing and tumor-promoting roles. However, EYA4 is the least well-characterized member of this unique family of PP, with its biological functions and molecular mechanisms in cancer progression, particularly in breast cancer, still largely unknown. In the present study, we found that the over-expression of EYA4 in breast tissue leads to an aggressive and invasive breast cancer phenotype, while the inhibition of EYA4 reduced tumorigenic properties of breast cancer cells in vitro and in vivo. Cellular changes downstream of EYA4, including cell proliferation and migration, may explain the increased metastatic power of breast cancer cells over-expressing EYA4. Mechanistically, EYA4 prevents genome instability by inhibiting the accumulation of replication-associated DNA damage. Its depletion results in polyploidy as a consequence of endoreplication, a phenomenon that can occur in response to stress. The absence of EYA4 leads to spontaneous replication stress characterized by the activation of the ATR pathway, sensitivity to hydroxyurea, and accumulation of endogenous DNA damage as indicated by increased γH2AX levels. In addition, we show that EYA4, specifically its serine/threonine phosphatase domain, plays an important and so far, unexpected role in replication fork progression. This phosphatase activity is essential for breast cancer progression and metastasis. Taken together, our data indicate that EYA4 is a novel potential breast cancer oncogene that supports primary tumor growth and metastasis. Developing therapeutics aimed at the serine/threonine phosphatase activity of EYA4 represents a robust strategy for killing breast cancer cells, to limit metastasis and overcome chemotherapy resistance caused by endoreplication and genomic rearrangements.

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Section: Discussionsupporting

confidence: 93%

EYA4 promotes breast cancer progression and metastasis through its role in replication stress avoidance

de la Peña Avalos,

Tropée,

Duijf

et al. 2023

Mol Cancer

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“…EYA4 promoter is covered with CpG island, and alternation of DNA methylation was observed in tumor samples compared to normal samples [ 17 , 30 ]. Additionally, abnormality of EYA4 expression has been mentioned to contribute to cancer progression for instance, colon cancer [ 31 ], glioma [ 32 ], lung cancer [ 23 ], and bladder cancer [ 26 ]. Also, downregulation of its expression was defined in different sets of colon cancers, suggesting its role in inhibiting tumor development [ 31 ].…”

Section: Discussionmentioning

confidence: 99%

Cigarette Smoke Regulates the Expression of EYA4 via Alternation of DNA Methylation Status

Almutairi

Alrefaei

et al. 2022

BioMed Research International

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Cigarette SMOKE (CS) considerably contributes to causing some diseases such as cancer, and it has a role in the alternation of gene expression through several mechanisms including epigenetics modification, particularly DNA methylation. EYA4 is one of the genes, that whose expression has been dysregulated in lung, colon, bladder, and breast cancer, leading to tumor progression. The alternation of DNA methylation levels has been implicated in regulating the expression of the EYA4 gene. Thus, in this study, we have shown the effect of CS on the DNA methylation level of the EYA4 promoter region as well as the methylation level on EYA4 expression. To determine the level of DNA methylation on the promoter region of the EYA4 gene, we have employed the bisulfite conversion treatment followed by the Sanger Sequence for 100 DNA samples taken from Saudi people (50 smokers and 50 nonsmokers). We found that 26% of DNA extracted from smoker samples is methylated, while there was no methylation identified in nonsmoker samples. Also, using the demethylating agents such as AZA on LoVo and Caco-2 cancer cell lines causes induction of transcription level of EYA4, implying the possible mechanism of DNA methylation in the upregulation of EYA4. These findings suggest the possible mechanism of CS in controlling the expression of EYA4 via changing the status of DNA methylation.

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“…For the latter, MITD1 was positively correlated to homologous recombination deficiency ( Dong et al, 2022 ). The gene Eyes absent homolog 4 ( EYA4 ) plays a putative tumor-promoting role in nervous system tumors ( Chong et al, 2023 ) and was found to promote cell proliferation in GBM ( Li et al, 2018b ). Transmembrane BAX inhibitor motif containing 6 ( TMBIM6 ) is elevated in GBM but may be downregulated in other tumor entities; it may be associated with tumor growth and dependent signaling ( Yi et al, 2023 ).…”

Section: Resultsmentioning

confidence: 99%

Molecular landscapes of glioblastoma cell lines revealed a group of patients that do not benefit from WWOX tumor suppressor expression

Kałuzińska-Kołat,

Kołat,

Kośla

et al. 2023

Front. Neurosci.

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IntroductionGlioblastoma (GBM) is notorious for its clinical and molecular heterogeneity, contributing to therapeutic failure and a grim prognosis. WWOX is one of the tumor suppressor genes important in nervous tissue or related pathologies, which was scarcely investigated in GBM for reliable associations with prognosis or disease progression despite known alterations. Recently, we observed a phenotypic heterogeneity between GBM cell lines (U87MG, T98G, U251MG, DBTRG-05MG), among which the anti-GBM activity of WWOX was generally corresponding, but colony growth and formation were inconsistent in DBTRG-05MG. This prompted us to investigate the molecular landscapes of these cell lines, intending to translate them into the clinical context.MethodsU87MG/T98G/U251MG/DBTRG-05MG were subjected to high-throughput sequencing, and obtained data were explored via weighted gene co-expression network analysis, differential expression analysis, functional annotation, and network building. Following the identification of the most relevant DBTRG-distinguishing driver genes, data from GBM patients were employed for, e.g., differential expression analysis, survival analysis, and principal component analysis.ResultsAlthough most driver genes were unique for each cell line, some were inversely regulated in DBTRG-05MG. Alongside driver genes, the differentially-expressed genes were used to build a WWOX-related network depicting protein–protein interactions in U87MG/T98G/U251MG/DBTRG-05MG. This network revealed processes distinctly regulated in DBTRG-05MG, e.g., microglia proliferation or neurofibrillary tangle assembly. POLE4 and HSF2BP were selected as DBTRG-discriminating driver genes based on the gene significance, module membership, and fold-change. Alongside WWOX, POLE4 and HSF2BP expression was used to stratify patients into cell lines-resembling groups that differed in, e.g., prognosis and treatment response. Some differences from a WWOX-related network were certified in patients, revealing genes that clarify clinical outcomes. Presumably, WWOX overexpression in DBTRG-05MG resulted in expression profile change resembling that of patients with inferior prognosis and drug response. Among these patients, WWOX may be inaccessible for its partners and does not manifest its anti-cancer activity, which was proposed in the literature but not regarding glioblastoma or concerning POLE4 and HSF2BP.ConclusionCell lines data enabled the identification of patients among which, despite high expression of WWOX tumor suppressor, no advantageous outcomes were noted due to the cancer-promoting profile ensured by other genes.

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EYA4 Promotes Cell Proliferation Through Downregulation of p27Kip1 in Glioma

Cited by 17 publications

References 32 publications

EYA4 promotes breast cancer progression and metastasis through its role in replication stress avoidance

EYA4 promotes breast cancer progression and metastasis through its role in replication stress avoidance

Cigarette Smoke Regulates the Expression of EYA4 via Alternation of DNA Methylation Status

Molecular landscapes of glioblastoma cell lines revealed a group of patients that do not benefit from WWOX tumor suppressor expression

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