Abstract:Management of neoangiogenesis remains a high-value therapeutic goal. A recently uncovered association between the DNA damage repair pathway and pathological angiogenesis could open previously unexplored possibilities for intervention. An attractive and novel target is the Eyes absent (EYA) tyrosine phosphatase, which plays a critical role in the repair versus apoptosis decision after DNA damage. This study examines the role of EYA in the postnatal development of the retinal vasculature and under conditions of … Show more
“…7a, d) possibly indicating ongoing DNA damage and repair in surviving PAECs through non-EYA3-dependent mechanisms. These trends are similar to those obtained in previous studies with other disease models where BZ treatment reduces the levels of DDR foci 24,29 .Fig. 7EYA-PTP inhibition reduces markers of DNA damage and repair.…”
Section: Resultssupporting
confidence: 90%
“…2f, g). To test the hypothesis that the EYA PTP activity might contribute to the ability of PAH-PASMC to survive DNA damage we used the previously characterized small molecule inhibitor benzarone (BZ) 24,27–29 . In the presence of BZ, PAH-PASMC survival after exposure to H 2 O 2 was reduced to levels comparable to that of normal PASMC (Fig.…”
Section: Resultsmentioning
confidence: 99%
“…Here we show that EYA3 is present in pulmonary vascular cells, and that EYA3 levels are elevated in pulmonary arterial smooth muscle cells (PASMC) from patients with PAH. Furthermore, inhibition of the EYA-PTP activity with Benzarone (BZ; a previously characterized EYA-PTP inhibitor 24,27–29 ) can both attenuate the development of experimental pulmonary hypertension and substantially reverse established pulmonary hypertension in a rodent model. Reduced levels of γ-H2AX foci, decreased proliferation and increased apoptosis are seen in lung tissue upon treatment with BZ.…”
In pulmonary hypertension vascular remodeling leads to narrowing of distal pulmonary arterioles and increased pulmonary vascular resistance. Vascular remodeling is promoted by the survival and proliferation of pulmonary arterial vascular cells in a DNA-damaging, hostile microenvironment. Here we report that levels of Eyes Absent 3 (EYA3) are elevated in pulmonary arterial smooth muscle cells from patients with pulmonary arterial hypertension and that EYA3 tyrosine phosphatase activity promotes the survival of these cells under DNA-damaging conditions. Transgenic mice harboring an inactivating mutation in the EYA3 tyrosine phosphatase domain are significantly protected from vascular remodeling. Pharmacological inhibition of the EYA3 tyrosine phosphatase activity substantially reverses vascular remodeling in a rat model of angio-obliterative pulmonary hypertension. Together these observations establish EYA3 as a disease-modifying target whose function in the pathophysiology of pulmonary arterial hypertension can be targeted by available inhibitors.
“…7a, d) possibly indicating ongoing DNA damage and repair in surviving PAECs through non-EYA3-dependent mechanisms. These trends are similar to those obtained in previous studies with other disease models where BZ treatment reduces the levels of DDR foci 24,29 .Fig. 7EYA-PTP inhibition reduces markers of DNA damage and repair.…”
Section: Resultssupporting
confidence: 90%
“…2f, g). To test the hypothesis that the EYA PTP activity might contribute to the ability of PAH-PASMC to survive DNA damage we used the previously characterized small molecule inhibitor benzarone (BZ) 24,27–29 . In the presence of BZ, PAH-PASMC survival after exposure to H 2 O 2 was reduced to levels comparable to that of normal PASMC (Fig.…”
Section: Resultsmentioning
confidence: 99%
“…Here we show that EYA3 is present in pulmonary vascular cells, and that EYA3 levels are elevated in pulmonary arterial smooth muscle cells (PASMC) from patients with PAH. Furthermore, inhibition of the EYA-PTP activity with Benzarone (BZ; a previously characterized EYA-PTP inhibitor 24,27–29 ) can both attenuate the development of experimental pulmonary hypertension and substantially reverse established pulmonary hypertension in a rodent model. Reduced levels of γ-H2AX foci, decreased proliferation and increased apoptosis are seen in lung tissue upon treatment with BZ.…”
In pulmonary hypertension vascular remodeling leads to narrowing of distal pulmonary arterioles and increased pulmonary vascular resistance. Vascular remodeling is promoted by the survival and proliferation of pulmonary arterial vascular cells in a DNA-damaging, hostile microenvironment. Here we report that levels of Eyes Absent 3 (EYA3) are elevated in pulmonary arterial smooth muscle cells from patients with pulmonary arterial hypertension and that EYA3 tyrosine phosphatase activity promotes the survival of these cells under DNA-damaging conditions. Transgenic mice harboring an inactivating mutation in the EYA3 tyrosine phosphatase domain are significantly protected from vascular remodeling. Pharmacological inhibition of the EYA3 tyrosine phosphatase activity substantially reverses vascular remodeling in a rat model of angio-obliterative pulmonary hypertension. Together these observations establish EYA3 as a disease-modifying target whose function in the pathophysiology of pulmonary arterial hypertension can be targeted by available inhibitors.
“…As in the case of tumor cells, the hypoxic environment can affect stromal cell behavior [ 116 ]. Endothelial cells are known to increase proliferation in response to a hypoxic environment and to activate a DDR signaling cascade similar to that described for tumor cells [ 117 – 119 ]. Accumulating evidence suggests that immune cell infiltration into the hypoxic tumor microenvironment increases angiogenesis and tumor metastasis [ 6 , 120 ].…”
Under hypoxic conditions, tumor cells undergo a series of adaptations that promote evolution of a more aggressive tumor phenotype including the activation of DNA damage repair proteins, altered metabolism, and decreased proliferation. Together these changes mitigate the negative impact of oxygen deprivation and allow preservation of genomic integrity and proliferative capacity, thus contributing to tumor growth and metastasis. As a result the presence of a hypoxic microenvironment is considered a negative clinical feature of many solid tumors. Hypoxic niches in tumors also represent a therapeutically privileged environment in which chemo- and radiation therapy is less effective. Although the negative impact of tumor hypoxia has been well established, the precise effect of oxygen deprivation on tumor cell behavior, and the molecular signals that allow a tumor cell to survive in vivo are poorly understood. Multicellular tumor spheroids (MCTS) have been used as an in vitro model for the avascular tumor niche, capable of more accurately recreating tumor genomic profiles and predicting therapeutic response. However, relatively few studies have used MCTS to study the molecular mechanisms driving tumor cell adaptations within the hypoxic tumor environment. Here we will review what is known about cell proliferation, DNA damage repair, and metabolic pathways as modeled in MCTS in comparison to observations made in solid tumors. A more precise definition of the cell populations present within 3D tumor models in vitro could better inform our understanding of the heterogeneity within tumors as well as provide a more representative platform for the testing of therapeutic strategies.
“…7,8 Recently, accumulating evidence has shown that EYA functions in the mediation of DNA repair, cell apoptosis, angiogenesis and tumor growth. [9][10][11][12][13] EYA4 was found to be epigenetically silenced and was reported to function as a potential tumor suppressor gene in various types of common human cancers such as esophageal adenocarcinoma, 14 breast cancer, 15 lung cancer 16 as well as in oral dysplasia. 17 In contrast, EYA4 has been reported to play an oncogenic role in peripheral nerve sheath tumors and breast cancer.…”
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.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
