Aberrant hypomethylation and overexpression of the eyes absent homologue 2 suppresses tumor cell growth of human lung adenocarcinoma cells

Gao, Tangxin; Zheng, Shangyong; Li, Qian; Ran, Pengzhan; Sun, Lijuan; Yao, Yuan; Xiao, Chunjie

doi:10.3892/or.2015.4245

Cited by 12 publications

(14 citation statements)

References 43 publications

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“…This result was consistent with a previous study of pancreatic carcinoma . However, the reported correlation in lung cancer cells and breast cancer cells was in contrast to our results. Furthermore, we observed a decrease in the enhancement of proliferation after expression of the H2A.X Y39F mutant (Fig.…”

Section: Resultssupporting

confidence: 89%

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Phosphorylation of H2A.X^T^yr39 positively regulates DNA damage response and is linked to cancer progression

et al. 2016

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Double‐stranded DNA breaks induce serine phosphorylation of histone H2A.X, producing γ‐H2A.X foci that are then recognized by DNA damage response pathway proteins. Formation of γ‐H2A.X is therefore critical for the repair of DNA double‐stranded breaks and maintenance of genomic stability, and defects in the recognition or repair of double‐stranded breaks can result in tumorigenesis. However, key details regarding the formation of γ‐H2A.X and its possible role in tumorigenesis remain elusive. Here, we report a previously unknown phosphorylation site on H2A.X, Tyr39. Phosphorylation at this site is induced by ionizing radiation and is a prerequisite for γ‐H2A.X formation. Increased phosphorylation of H2A.X at Tyr39 was observed in multiple cancer cell lines, and we found that H2AX Tyr39 phosphorylation positively correlated with histological grade, tumor size and tumor node metastasis stage, and negatively correlated with survival. We also identified a potential role for eyes absent 2 (EYA2) in regulating H2A.X Tyr39 phosphorylation. Our study supports an important role for H2AX Tyr39 phosphorylation in γ‐H2A.X formation and cancer progression.

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Section: Resultssupporting

confidence: 89%

“…This result was consistent with a previous study of pancreatic carcinoma [19]. However, the reported correlation in lung cancer cells [20] and breast cancer cells H2A.X Y39ph is involved in the regulation of DDR. (A) Histone proteins were extracted from HCT15 cells after 2 Gy IR exposure.…”

Section: Eya2 Dephosphorylates H2ax Tyr39supporting

confidence: 93%

Phosphorylation of H2A.X^T^yr39 positively regulates DNA damage response and is linked to cancer progression

et al. 2016

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“… 37 The EYA2 gene is hypomethylated in lung cancer cells, resulting in EYA2 overexpression. 36 We showed that miR-338-3p directly inhibited EYA2 expression at the post-transcriptional level in cultured cancer cells and its expression negatively correlated with EYA2 expression in breast cancer patients. Moreover, we demonstrated that, through EYA2 inhibition, miR-338-3p not only suppressed breast cancer cell proliferation, EMT, migration and invasion in vitro , but also prevented breast cancer cell metastasis to lung in vivo .…”

Section: Discussionmentioning

confidence: 81%

“…33 EYA2 expression has been shown to be overexpressed in a variety of cancers, including breast cancer, ovarian cancer and lung cancer, and its overexpression is correlated with poor prognosis. 34 , 35 , 36 EYA2 increases proliferation, migration, invasion, and metastasis in breast cancer cells. EYA2 is also involved in stimulation of EMT, a process important for cancer cell migration, invasion, and metastasis.…”

Section: Discussionmentioning

confidence: 96%

The EGFR/miR-338-3p/EYA2 axis controls breast tumor growth and lung metastasis

Liang¹,

Xu²,

Wang

et al. 2017

Cell Death Dis

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Dysregulation of the epidermal growth factor receptor (EGFR) promotes cancer cell growth, invasion and metastasis. However, its relevant downstream effectors are still limited. Here, we show that EGFR promotes breast tumor growth and metastasis by downregulating the tumor suppressor micoRNA-338-3p (miR-338-3p) and activating the EYA2 (EYA transcriptional coactivator and phosphatase 2) oncoprotein. EGFR represses miR-338-3p expression largely through HIF1α transcription factor. miR-338-3p inhibits EYA2 expression by binding to the 3′-untranslated region of EYA2. EGFR increases EYA2 expression via HIF1α repression of miR-338-3p. Through the miR-338-3p/EYA2 pathway, EGFR increases breast cancer cell growth, epithelial-to-mesenchymal transition, migration, invasion and lung metastasis in vitro and in a allograft tumor mouse model in vivo. In breast cancer patients, miR-338-3p expression negatively correlates with the expression of EGFR and EYA2, EGFR status positively associates with EYA2 expression, and miR-338-3p and EYA2 predict breast cancer lung metastasis when expressed in primary breast cancers. These data suggest that the miR-338-3p/ EYA2 axis contributes to EGFR-mediated tumor growth and lung metastasis and that miR-338-3p activation or EYA2 inhibition or combination therapy targeting EGFR/miR-338-3p/EYA2 axis may be a promising way to treat patients with metastatic cancer. Cell Death and Disease (2017) 8, e2928; doi:10.1038/cddis.2017.325; published online 13 July 2017The epidermal growth factor receptor (EGFR) is a member of the ErbB (avian erythroblastosis oncogene B) family of receptors and activates multiple signaling pathways, including mitogen-activated protein kinase (MAPK)/extracellular signalregulated kinases (ERK) and phosphoinositide-3-kinase (PI3K)/V-AKT murine thymoma viral oncogene homolog (AKT) pathways. 1-3 EGFR activation regulates many biological processes, such as cell proliferation, invasion, metastasis and apoptosis. [4][5][6] EGFR is overexpressed in various human cancers, including lung cancer, breast cancer, colon cancer and glioblastoma, and is associated with tumor malignancy and poor prognosis. 7-10 Thus, EGFR and its downstream signaling effectors have become targets for cancer therapy. 11 Approximately 90% of deaths associated with cancer are due to distant metastases. 12 Many cancers can metastasize anywhere in body but primarily metastasizes to some organs or tissues. For instance, lungs and bones are frequent sites of breast cancer metastasis. Although EGFR dysregulation enhances cancer metastasis, the relevant downstream effectors are largely unknown.MicroRNAs (miRNAs) are small noncoding RNA molecules (about 22 nucleotides in length), which function in RNA silencing and post-transcriptional regulation of gene expression. miRNAs participate in many biological processes, such as cell proliferation, invasion, metastasis, and apoptosis. 13 Recently, EGFR has been shown to promote prostate cancer bone metastasis by decreasing the expression of miR-1, a tumor suppressor, and inc...

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“…The EYA2 is critical for PLZF-RARA-induced leukemogenesis [ 16 ]. Moreover, EYA2 has been shown to promote cell growth in lung cancer [ 17 ]. EGFR/miR-338-3p/EYA2 axis controls breast tumor growth and lung metastasis [ 18 ].…”

Section: Introductionmentioning

confidence: 99%

EYA2 promotes lung cancer cell proliferation by downregulating the expression of PTEN

Qiu

Xia³

et al. 2017

Oncotarget

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Lung cancer is the leading cause of cancer-related death worldwide. Despite advances have been made in diagnosis and therapeutic strategies, the prognosis of lung cancer is still very poor. Eyes absent transcriptional cofactor EYA2 has been shown to promote lung cancer cell growth, however, the underlying molecular mechanism is still not fully understood. In the present study, we found that EYA2 was up-regulated in lung cancer, and EYA2 led to increased cell proliferation by inhibiting Phosphatase and tensin homologue (PTEN) expression via modulation of miR-93. Additionally, survival analysis showed that lung cancer patients with higher EYA2 expression predicted a worse prognosis. Therefore, these findings demonstrate that EYA2 may play an important role in lung cancer occurrence and progression. Targeting EYA2 may provide a feasible approach in developing novel anticancer therapeutics.

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Aberrant hypomethylation and overexpression of the eyes absent homologue 2 suppresses tumor cell growth of human lung adenocarcinoma cells

Cited by 12 publications

References 43 publications

Phosphorylation of H2A.X^T^yr39 positively regulates DNA damage response and is linked to cancer progression

Phosphorylation of H2A.X^T^yr39 positively regulates DNA damage response and is linked to cancer progression

The EGFR/miR-338-3p/EYA2 axis controls breast tumor growth and lung metastasis

EYA2 promotes lung cancer cell proliferation by downregulating the expression of PTEN

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Aberrant hypomethylation and overexpression of the eyes absent homologue 2 suppresses tumor cell growth of human lung adenocarcinoma cells

Cited by 12 publications

References 43 publications

Phosphorylation of H2A.XTyr39 positively regulates DNA damage response and is linked to cancer progression

Phosphorylation of H2A.XTyr39 positively regulates DNA damage response and is linked to cancer progression

The EGFR/miR-338-3p/EYA2 axis controls breast tumor growth and lung metastasis

EYA2 promotes lung cancer cell proliferation by downregulating the expression of PTEN

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Phosphorylation of H2A.X^T^yr39 positively regulates DNA damage response and is linked to cancer progression

Phosphorylation of H2A.X^T^yr39 positively regulates DNA damage response and is linked to cancer progression