Ubiquitously Expressed Hematological and Neurological Expressed 1 Downregulates Akt-Mediated GSK3β Signaling, and Its Knockdown Results in Deregulated G2/M Transition in Prostate Cells

Varisli, Lokman; Gonen-Korkmaz, Ceren; Debelec-Butuner, Bilge; Erbaykent-Tepedelen, Burcu; Muhammed, Hamid Syed; Böğürcü, Nuray; Saatcioglu, Fahri; Korkmaz, Kemal

doi:10.1089/dna.2010.1128

Cited by 32 publications

(56 citation statements)

References 48 publications

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“…Further, activated Akt stabilizes β-catenin via inhibition of GSK3β [34] and directly phosphorylates β-catenin at S552, thereby promotes β-catenin transactivation [9]. Based on previous reports [35] and our findings reported here, we suggest that mimicking TNFα-mediated inflammation [20] in prostate cells results in a significant increase in pAkt (S473) , which consequently inhibits GSK3β kinase activity by increasing the phosphorylation from (S9) residue (Figure 1E). Furthermore, the decrease in β-catenin (S33) phosphorylation implies that either proteosomal degradation is activated and β-catenin (S33) is depleted by ubiquitination dependent proteosomal machinery, or there can be an increase in the stabilizing phosphorylation of β-catenin (S552) , which suppresses the S33 phosphorylation (Figure 1E) by enhanced Akt activity.…”

Section: Discussionsupporting

confidence: 78%

TNFα-Mediated Loss of β-Catenin/E-Cadherin Association and Subsequent Increase in Cell Migration Is Partially Restored by NKX3.1 Expression in Prostate Cells

et al. 2014

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Inflammation-induced carcinogenesis is associated with increased proliferation and migration/invasion of various types of tumor cells. In this study, altered β-catenin signaling upon TNFα exposure, and relation to loss of function of the tumor suppressor NKX3.1 was examined in prostate cancer cells. We used an in vitro prostate inflammation model to demonstrate altered sub-cellular localization of β-catenin following increased phosphorylation of Akt(S473) and GSK3β(S9). Consistently, we observed that subsequent increase in β-catenin transactivation enhanced c-myc, cyclin D1 and MMP2 expressions. Consequently, it was also observed that the β-catenin-E-cadherin association at the plasma membrane was disrupted during acute cytokine exposure. Additionally, it was demonstrated that disrupting cell-cell interactions led to increased migration of LNCaP cells in real-time migration assay. Nevertheless, ectopic expression of NKX3.1, which is degraded upon proinflammatory cytokine exposure in inflammation, was found to induce the degradation of β-catenin by inhibiting Akt(S473) phosphorylation, therefore, partially rescued the disrupted β-catenin-E-cadherin interaction as well as the cell migration in LNCaP cells upon cytokine exposure. As, the disrupted localization of β-catenin at the cell membrane as well as increased Akt(S308) priming phosphorylation was observed in human prostate tissues with prostatic inflammatory atrophy (PIA), high-grade prostatic intraepithelial neoplasia (H-PIN) and carcinoma lesions correlated with loss of NKX3.1 expression. Thus, the data indicate that the β-catenin signaling; consequently sub-cellular localization is deregulated in inflammation, associates with prostatic atrophy and PIN pathology.

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Section: Discussionsupporting

confidence: 78%

TNFα-Mediated Loss of β-Catenin/E-Cadherin Association and Subsequent Increase in Cell Migration Is Partially Restored by NKX3.1 Expression in Prostate Cells

et al. 2014

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“…Here, our results demonstrated that frequently up-regulated miR-132 in breast cancer influence cancer cell behavior by targeting HN1. HN1 expression is high in various carcinomas, while low in benign tumors [13]. In general, HN1 is an interaction partner of the inactive GSK3b/b-catenin/APC complex, which promotes ubiquitin-dependent proteasomal degradation of b-catenin, and contributes to migration in prostate cancer [15].…”

Section: Discussionmentioning

confidence: 99%

“…HN1 was detected as an oncogene in some cancers. Depletion of HN1 in both melanoma and prostate cells results in cell cycle arresting-related proliferation suppression [12,13]. Moreover, in vitro and in vivo studies demonstrated that overexpressing HN1 promotes wound healing in prostate cancer [14].…”

Section: Introductionmentioning

confidence: 99%

MiR-132 prohibits proliferation, invasion, migration, and metastasis in breast cancer by targeting HN1

Zhang

Chen

et al. 2014

Biochemical and Biophysical Research Communications

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“…Side population analysis was performed according to the previous report [16]. Cell analysis using FACSCalibur cytometer (Becton Dickinson).…”

Section: Methodsmentioning

confidence: 99%

HN1 contributes to migration, invasion, and tumorigenesis of breast cancer by enhancing MYC activity

Zhang

et al. 2017

Mol Cancer

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BackgroundHematological and neurological expressed 1 (HN1) is upregulated in many tumors, but the role of HN1 in breast cancer progression and its regulatory mechanism have not been well understood.MethodsTo study the role of HN1 in the initiation and progression of breast cancer, we examined HN1 levels in breast cancer cells and tissues and analyzed the relationship between HN1 levels and patient survival. We used mammosphere formation assay, side population analysis, wound healing assay, transwell assay, soft agar formation assay, and xenografted tumor model to determine the effect of HN1 on the expansion of breast cancer stem cells, and the migration, invasion and tumorigenesis of breast cancer. To determine whether HN1 regulates MYC, we used quantitative real-time PCR and Western blot analysis to assess the expression of MYC and their targeted genes to determine the phenotype caused by knockdown of MYC in breast cancer cell with HN1 overexpression.ResultsIn this study, we found that HN1 was upregulated in breast cancer tissues. Patients with high levels of HN1 expression had significantly shorter survival than those with low HN1 expression. In breast cancer cell line, ectopic overexpression of HN1 not only promoted the expansion of breast cancer stem cells, but also promoted cell migration, invasion, and tumorigenesis, while knockdown of HN1 reduced these effects. Furthermore, there was a positive correlation between MYC (also known as c-MYC) level and HN1 level, mechanism analysis suggested HN1 promoted the expression of MYC and its targeted genes like CDK4, CCND1, p21, CAV1, and SFRP1. Downregulation of MYC abrogated the effect of HN1 overexpression in breast cancer cell lines.ConclusionTaken together, these data reveal that HN1 promotes the progression of breast cancer by upregulating MYC expression, and might be a therapeutic target for breast cancer.Electronic supplementary materialThe online version of this article (doi:10.1186/s12943-017-0656-1) contains supplementary material, which is available to authorized users.

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Ubiquitously Expressed Hematological and Neurological Expressed 1 Downregulates Akt-Mediated GSK3β Signaling, and Its Knockdown Results in Deregulated G2/M Transition in Prostate Cells

Cited by 32 publications

References 48 publications

TNFα-Mediated Loss of β-Catenin/E-Cadherin Association and Subsequent Increase in Cell Migration Is Partially Restored by NKX3.1 Expression in Prostate Cells

TNFα-Mediated Loss of β-Catenin/E-Cadherin Association and Subsequent Increase in Cell Migration Is Partially Restored by NKX3.1 Expression in Prostate Cells

MiR-132 prohibits proliferation, invasion, migration, and metastasis in breast cancer by targeting HN1

HN1 contributes to migration, invasion, and tumorigenesis of breast cancer by enhancing MYC activity

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