Targeting EYA3 in Ewing Sarcoma Retards Tumor Growth and Angiogenesis

Wang, Yuhua; Pandey, Ram Naresh; Roychoudhury, Kaushik; Milewski, David; Kalin, Tanya V.; Szabo, Sara; Pressey, Joseph G.; Hegde, Rashmi S.

doi:10.1158/1535-7163.mct-20-0749

Cited by 11 publications

(10 citation statements)

References 39 publications

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“…Many decades after Drosophila EYA was first described, insights into the roles of EYAs in normal development, physiology and disease continue to emerge. Not described here, but of emerging clinical importance, is the therapeutic potential of targeting the EYA PTP activity for diseases ranging from cancer [82][83][84] to pulmonary arterial hypertension [85] and proliferative retinopathies [35]. Much remains to be clarified regarding EYA protein function and regulation.…”

Section: Discussionmentioning

confidence: 99%

The Eyes Absent proteins in development and in developmental disorders

Soni

Roychoudhury

Hegde

2021

Biochemical Society Transactions

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The Eyes Absent (EYA) transactivator-phosphatase proteins are important contributors to cell-fate determination processes and to the development of multiple organs. The transcriptional regulatory activity as well as the protein tyrosine phosphatase activities of the EYA proteins can independently contribute to proliferation, differentiation, morphogenesis and tissue homeostasis in different contexts. Aberrant EYA levels or activity are associated with numerous syndromic and non-syndromic developmental disorders, as well as cancers. Commensurate with the multiplicity of biochemical activities carried out by the EYA proteins, they impact upon a range of cellular signaling pathways. Here, we provide a broad overview of the roles played by EYA proteins in development, and highlight the molecular signaling pathways known to be linked with EYA-associated organ development and developmental disorders.

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Section: Discussionmentioning

confidence: 99%

The Eyes Absent proteins in development and in developmental disorders

Soni

Roychoudhury

Hegde

2021

Biochemical Society Transactions

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“…The progression of a continuous cell cycle and DNA damage repair mechanism is highly upregulated in Ewing sarcoma tumors. This is due to the activity of the EYA3 protein which encourages tumor growth and angiogenesis (Wang et al, 2021). EWS-FLI is the master regulatory and faulty fusion protein which promotes the oncogenesis in EWS cells and upregulates the activity of EYA3 by inhibiting miRNA-708 (Robin et al, 2012).…”

Section: Discussionmentioning

confidence: 99%

“…This protein plays a vital role during embryogenic development, and afterwards its activity is silenced after development. Recently, Wang and colleagues studied the molecular mechanism of Ewing sarcoma in the A673 cell line (Wang et al, 2021). They have identified the upregulation of EYA3 by EWS-FLI fusion protein, expediting cell division and tumor growth.…”

Section: Inhibitors Of Eya3 Protein In Ewing Sarcomamentioning

confidence: 99%

“…According to Wang et al, (2021), inhibited the EYA3 We took the similar approach, by using A673 in the PaccMann database to evaluate the cytotoxic effects of these compounds (Table 6). Sorbifolin induced cytotoxicity in A673 cells, using hydroxyl and oxy groups along with carbon of its benzene rings: the IC50 value recorded was 2.48 log(µmol) whereas 1,7-dihydroxy-3methylanthracene-9.10-dione also induced cytotoxicity by using oxy groups and carbons of anthracene.…”

Section: Cell Lining Studiesmentioning

confidence: 99%

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Inhibitors of EYA3 Protein in Ewing Sarcoma

Shah

Kim

2022

Asian Pac J Cancer Prev

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Objective: Among sarcomas, Ewing sarcoma (EWS) is characterized as a highly malignant type of bone tumor caused by the fusion of EWS RNA Binding Protein-1 (EWSR1)/ Friend leukemia integration 1 (FLI1) genes. The product of fusion gene gives rise to EWSR1/FLI1 which activates the activity of Eyes absent homolog 3 (EYA3) which causes tumor growth and angiogenesis. EYA3 is now considered as a therapeutic drug target for EWS . The study was designed to gather potential inhibitors for the EYA3 target using medicinal compounds. Methods: In this study, we have obtained a list of medicinal compounds from the NuBBE database and downloaded their structural information. Then insilico screening analysis of >2,000 medicinal compounds was performed with PyRX virtual drug screening software to discover potential inhibitors for the treatment of EWS. Results: Our investigation revealed that Sorbifolin and 1,7-Dihydroxy-3-methylanthracene-9.10-dione show interactive affinity for EYA3 active residues. Moreover, these compounds have adequate toxicity, can induce cytotoxicity in EWS cells, and are capable of regulating the expression of genes activated by EWSR1/FLI1. Conclusion: Our study concluded that Sorbifolin and 1,7-Dihydroxy-3-methylanthracene-9.10-dione are promising drug candidates for the treatment of EWS and should be further subjected to invitro testing.

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“…The Eyes Absent Family (EYA1-4) are a unique group of dual-function proteins with oncogenic roles in a variety of tumour types, where they promote cancer cell phenotypes such as proliferation, survival and migration [1][2][3][4][5][6][7][8][9] . EYA proteins possess N-terminal transcriptional coactivation activity and C-terminal Haloacid Dehydrogenase (HAD) protein tyrosine phosphatase activity 5,[10][11][12][13][14][15][16][17][18][19] . EYAs are the only known HAD-family tyrosine phosphatases and have unique active site chemistry making them well suited to specific inhibition with small molecules [20][21][22][23] .…”

Section: Introductionmentioning

confidence: 99%

The Eyes Absent family members EYA4 and EYA1 promote PLK1 activation and successful mitosis through tyrosine dephosphorylation

Nelson

Rogers

Roychoudhury

et al. 2022

Preprint

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The Eyes Absent family of proteins (EYA1-4) are a biochemically unique group of tyrosine phosphatases known to be tumour promoting across a range of cancer types. To date, the molecular targets of EYA phosphatase activity remain largely uncharacterised. Here, we identify Polo-like kinase 1 (PLK1) as a direct interactor and phosphatase substrate of both EYA4 and EYA1, with pY445 on PLK1 being the primary target site. EYA-mediated dephosphorylation of PLK1 in the G2 phase of the cell cycle is required for centrosome maturation, PLK1 localization to centrosomes, and polo-box domain (PBD) dependent interactions between PLK1 and the PLK1-activating proteins BORA and CEP192. Molecular dynamics simulations support the rationale that pY445 confers a structural impairment to PBD-substrate interactions that is relieved by EYA-mediated dephosphorylation. Depletion of EYA4 or EYA1, or chemical inhibition of EYA phosphatase activity, dramatically reduces PLK1 activation, causing mitotic defects and cell death. Overall, we have characterized a novel phosphotyrosine signalling network governing PLK1 and mitosis. This work provides a mechanism of cell killing for EYA phosphatase inhibitors with important therapeutic implications.

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Targeting EYA3 in Ewing Sarcoma Retards Tumor Growth and Angiogenesis

Cited by 11 publications

References 39 publications

The Eyes Absent proteins in development and in developmental disorders

The Eyes Absent proteins in development and in developmental disorders

Inhibitors of EYA3 Protein in Ewing Sarcoma

The Eyes Absent family members EYA4 and EYA1 promote PLK1 activation and successful mitosis through tyrosine dephosphorylation

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