Browsing by Subject "ATAD2"

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    Analysis of the ATAD2 gene effect on the genes involved in epithelial mesenchymal transition in estrogen positive and negative breast cancers
    (2021-02) Özerk, Zeynep Ilgım
    ATAD2 is overexpressed in many distinct cancer types including breast cancer. Its elevated expression is an indicator of poor prognosis. High ATAD2 expression correlates with short overall survival, disease-free survival as well as shorter recurrence-free survival. Moreover, ATAD2 is associated with migration and invasion in some cancer types such as hepatocellular carcinoma and cervical cancer. In breast cancer, ATAD2 expression is higher in invasive tumors. ATAD2 is coactivator of steroid hormone receptor ERα. It directly interacts with ERα and enhances its target genes expressions. ERα is also a regulator of EMT in breast carcinomas. Based on our current knowledge it is proposed that ATAD2 may have a role in EMT and migration capacity of breast cancer cells and this role may be ER dependent as both ATAD2 and EMT are associated with ERα. Bioinformatics analysis revealed that siATAD2 silencing decreased mesenchymal gene expressions significantly in MCF7 and T47D cells. To investigate the possible mesenchymal inducing role of ATAD2, ATAD2 was silenced with shRNA transfection in ER+ MCF7 and T47D cells and ER- mda-mb-231 and sk-br-3 cells. ATAD2 silencing decreased mesenchymal markers expression at both the mRNA and protein level in ER- cells. In ER+ cells, no change in EMT marker proteins and mRNAs were observed with ATAD2 silencing. ER was silenced in ER+ cells and ER silencing introduced a mesenchymal phenotype to them. In this case, ATAD2 silencing reduced this mesenchymal phenotype introduced with ER loss. The EMT effect of the ATAD2 silencing on migration capacity of breast cancer cells was assessed with a scratch assay. Consistent with changes in the epithelial and mesenchymal markers, ATAD2 silencing reduced the migration capacity of mda-mb-231 cells. On the other hand, sk-br-3 migration did not change significantly. In ER+ cells ATAD2 silencing alone had no influence on migratory capacity. ER silencing increased their migration significantly while ATAD2 downregulation in ER-silenced cells suppressed this migration. Over all, this study suggests a possible involvement of ATAD2 in EMT and migration regulation in ER- cells. Targeting ATAD2 in ER- mesenchymal breast cancer cells could be a strategy to reduce their migration capacity.
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    Evaluation of ATAD2 as a potential target in hepatocellular carcinoma
    (Springer, 2021-11-05) Gürsoy Yüzügüllü, Özge; Ekin, U.; Özen, C.; Korhan, P.; Bağırsakcı, E.; Yılmaz, F.; Uzuner, H.; Alotaibi, H.; Kırmızıbayrak, P. B.; Atabey, N.; Karakülah, G.; Öztürk, M.; Yüzügüllü, Haluk
    Purpose Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death worldwide with lack of effec-tive systemic chemotherapy. In this study, we aimed to evaluate the value of ATPase family AAA domain-containing protein 2 (ATAD2) as a biomarker and potential therapeutic target for HCC.Methods The expression of ATAD2 was tested in different HCC patient cohorts by immunohistochemistry and comparative transcriptional analysis. The co-expression of ATAD2 and proliferation markers was compared during liver regeneration and malignancy with different bioinformatics tools. The cellular effects of ATAD2 inactivation in liver malignancy was tested on cell cycle, apoptosis, and colony formation ability as well as tumor formation using RNA interference. The genes affected by ATAD2 inactivation in three different HCC cell lines were identified by global gene expression profiling and bioinformatics tools.Results ATAD2 overexpression is closely correlated with HCC tumor stage. There was gradual increase from dysplasia, well-differentiated and poorly-differentiated HCC, respectively. We also observed transient upregulation of ATAD2 expres-sion during rat liver regeneration in parallel to changes in Ki-67 expression. ATAD2 knockdown resulted in apoptosis and decreased cell survival in vitro and decreased tumor formation in some HCC cell lines. However, three other HCC cell lines tested were not affected. Similarly, gene expression response to ATAD2 inactivation in different HCC cell lines was highly heterogeneous.Conclusions ATAD2 is a potential proliferation marker for liver regeneration and HCC. It may also serve as a therapeutic target despite heterogeneous response of malignant cells.
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    Functional effects of ATAD2 gene expression in breast cancer
    (2016-08) Özel, Buse Nurten
    The ATAD2 gene is a newly investigated gene of which the expression levels are associated with the disease prognosis in many types of cancer and especially breast cancer and that is known to be overexpressed usually through gene amplification and E2F/RB pathway activation. ATAD2 (ATPase family, AAA domain-containing 2) can be overexpressed due to amplification or other regulatory mechanisms in many cancers such as lung, breast, prostate and liver. The fact that ATAD2 has an AAA+ ATPase and bromodomain indicates that it may be a good target for anti-cancer therapy. However, it is necessary to clarify the role of the ATAD2 gene in tumorigenesis before strategies that target ATAD2 are developed. We evaluated a regulator that consistently shows high expression in breast cancer in this study. ATAD2 (ATPase family AAA domain-containing protein 2) is a gene that regulates important cellular activities such as cell proliferation and invasion. This study aimed to clarify the mechanism of action of ATAD2 in breast cancer. The ATAD2 expression of the MCF7 and T47D cell lines with high ATAD2 gene expression was silenced with siRNA and the expression levels of all genes were screened. Gene chip expression analyses revealed that the suppression of ATAD2 in breast cancer cells indicated a role in the regulation of microtubule organization, cell growth, cell adhesion and important signal pathways such as EGFR, FGFR, MAPK, and PI3K. Functional studies with breast cancer cells have supported the gene expression analysis results. Our study revealed that silencing of ATAD2 lead to suppression of ER(-) breast cancer cell migration but not ER(+) cancer cell migration. The same experiments causes a marked decrease in the colony formation capacity and proliferation potential of HCC1937 cells while there was no change in SKBR3 and ER(+) cells. ATAD2 silencing also lead to a senescence response in all breast cancer cells. We investigated the molecular mechanisms of action of ATAD2 to determine the factors underlying the biological effect. The MCF7 and HCC1937 cells were used to clarify its action on the main cellular signal pathways. We found that ATAD2 silencing induced an apoptosis response in both cell types. Intrinsic pathways are activated with caspase-9 cleavage in MCF7 cells while high Bcl2 and BclXL expression prevents caspase-9 cleavage in HCC1937 cells. Decreased ATAD2 did not cause a difference in the p53 protein level in either cells but while p21 expression was increased in just MCF7 cells, RB phosphorylation was inhibited in both cell lines. The results indicate that dysregulation of proteins involved in intracellular control pathways triggers the senescence mechanism. ERα gene expression has been shown to be suppressed as a result of siRNA suppression of ATAD2 gene expression in MCF7 cells. This result indicates that ATAD2 has a role in ERα regulation. ATAD2 gene expression has been found to decrease following Gefitinib suppression of EGFR signaling while EGF treatment of serum-starved MCF7 cells caused increased ATAD2 gene expression. These results indicate that EGFR could be a possible upstream activator of ATAD2. This gene expression pattern also points towards a positive feedback mechanism between ATAD2+ERα and EGFR. Although it is known that EGFR is frequently overexpressed in breast cancer and cross-talk with the estrogen receptor, we do not have detailed information on the mechanism of their interactions. ‘Pathway Enrichment’ analysis of microarray studies have revealed EGFR signaling as one of pathways enriched in the genes downregulated with decreased ATAD2 expression. The silencing of ATAD2 and ERα together prevents EGFR expression in MCF7 cells while silencing of ATAD2 by itself in HCC1937 cells does not cause a change in EGFR expression but prevents its phosphorylation in the Tyr1173 region of the receptor. The ATAD2-suppressed EGFR activity in HCC1937 cells did not lead any change in the Akt level or MEK/ERK activity. The down-stream signaling pathway analysis of the EGFR has revealed that Akt protein expression is suppressed when ATAD2 is silenced in MCF7 cells. The increase in the MEK/ERK signaling activity with decreased ERα expression in the same cells was suppressed with decreased ATAD2 expression. In conclusion, the high expression of the ATAD2 gene in breast cancer stimulates growth of cancer cells while its interaction with the EGFR signaling pathway could be one of the causes of the pro-oncogenic effects of the gene. Its suppression together with EGFR could provide an option for new therapeutic applications in breast cancer studies.