Androgen regulated HN1 leads proteosomal degradation of androgen receptor (AR) and negatively influences AR mediated transactivation in prostate cells

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

doi:10.1016/j.mce.2011.11.027

Cited by 33 publications

(49 citation statements)

References 38 publications

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“…The segregation of AR-positive cases to the MErT and hybrid/partial EMT classes underlines a previously unreported discrepancy between the degree of differentiation (in terms of morphology and immunophenotype) and stemness, which may explain the poor response of DSRCTs to target treatments [37]. The absence of the nuclear co-localisation of AR and β-catenin despite the overlapping between the AR and β-catenin profiles is likely to be due to the HNI-mediated stabilisation of β-catenin and its interaction with E-cadherin [38,39]. Furthermore, unlike others [40] we did not observe an inverse correlation between AR activation and E-cadherin downregulation.…”

Section: Discussionmentioning

confidence: 99%

New transcriptional-based insights into the pathogenesis of desmoplastic small round cell tumors (DSRCTs)

et al. 2017

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To gain new insights into desmoplastic small round cell tumors (DSRCTs) by means of gene expression profiling (GEP). Formalin-fixed, paraffin-embedded surgical specimens obtained from seven pretreated DSRCT patients were interrogated using GEP complemented by immunohistochemistry, a cancer stem cell array, and miRNA in situ hybridisation, including the combined chimera modules miRNA-200/ZEB1 and miRNA-34/SLUG. The chimera modules divided the cases into three classes that respectively recapitulated the traits of mesenchymal epithelial reverse transition (MErT), epithelial mesenchymal transition (EMT), and hybrid/partial EMT. This indicates a close correlation between the reprogramming governed by EMT regulators and DSRCT biology, which was further confirmed by miRNA-21 and is consistent with the broad morphological spectrum of DSRCTs. Starting from the miRNA-200/ZEB1 axis, we also found that DSRCTs carry a signature of immunological ignorance that is not responsive to PD-L1 blockade. Evidence that the up-regulation of miRNA-200 and E-cadherin, and quite a high level of miRNA-21 expression segregate with the MErT supports the idea that, in addition to the hybrid/partial state, MErT is also enriched in stemness: the androgen-positive cases, whose stemness traits were confirmed by stem cell arrays, all fell into these two classes. Our findings also confirmed that tumoral cell PDGFRA expression correlates with desmoplasia, and demonstrated the co-expression of PDGFRA and ISLR/Meflin, another marker of pluripotency. Despite the limited number of cases, these findings provide unexpectedly relevant information concerning the pathogenesis of DSRCTs, and prove the validity of miRNA-based chimera circuit modelling in the clinico-pathological setting.

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Section: Discussionmentioning

confidence: 99%

New transcriptional-based insights into the pathogenesis of desmoplastic small round cell tumors (DSRCTs)

et al. 2017

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“…At least two kinases, Akt and PIM-1, are known to phosphorylate S213 with different functional consequences (Wen et al 2000; Lin et al 2001; Lin et al 2003; Taneja et al 2005; Palazzolo et al 2007; Ha et al 2012; Kasina & Macoska 2012; Linn et al 2012; Varisli et al 2012). Moreover, Akt-dependent AR S213 phosphorylation is regulated by several signaling pathways (Wen et al 2000; Kasina & Macoska 2012; Varisli et al 2012). Different functional consequences including effects on AR stability, AR transactivation, and prostate cancer cell growth depending on the context of regulation were reported for the AR S213 phosphorylation.…”

Section: S213 S791 and T850 Phosphorylationmentioning

confidence: 99%

Androgen receptor phosphorylation: biological context and functional consequences

Koryakina¹,

Ta²,

Gioeli³

2014

Endocrine-Related Cancer

121

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The androgen receptor (AR) is a ligand-regulated transcription factor that belongs to the family of nuclear receptors. In addition to regulation by steroid, the AR is also regulated by post-translational modifications generated by signal transduction pathways. Thus, the AR functions not only as transcription factor, but also as a node that integrates multiple extracellular signals. The importance of the AR in disease cannot be understated as it plays a role in many diseases ranging from complete androgen insensitivity syndrome to spinal bulbar muscular atrophy to prostate and breast cancer. In the case of prostate cancer, dependence on AR signaling has been exploited for therapeutic intervention for decades. However, the effectiveness of these therapies is limited in advanced disease due to restoration of AR signaling. Fully understanding the molecular mechanisms of AR action will enable the development of future therapeutics for the wide range of AR dependent diseases. The AR is subject to regulation by a number of kinases through post-translational modifications on serine, threonine and tyrosine residues. Here we review the AR phosphorylation sites, the kinases responsible for these phosphorylations, as well as the biological context and the functional consequences of these phosphorylations. Finally, what is known about the state of AR phosphorylation in clinical samples is discussed.

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“…Cell proliferation was measured using WST-1 assay kit (BioVision, USA) at designated time points, and relative proliferation was calculated by normalizing to day 1 values. Colony formation assays were performed as described previously [20]. Briefly, PC-3, DU145, and LNCaP cells were transfected with an empty vector or an EFS.…”

Section: Antibodies and Immunoblottingmentioning

confidence: 99%

“…Colonies were stained with crystal violet (0.2 %), and the area covered on each plate by the colonies was measured using a colony counter software program [21]. An in vitro wound-healing model (streak assay) was used to detect migration differences between vector and EFStransfected PC-3 cells, as described previously [20]. In this assay, sub-confluent PC-3 cells were transfected with vector or EFS, and 24 h later, confluent cells were scarped with a blue pipette tip and rinsed with PBS to remove any floating cells.…”

Section: Antibodies and Immunoblottingmentioning

confidence: 99%

Decreased expression of EFS is correlated with the advanced prostate cancer

et al. 2014

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Prostate cancer is the most frequently diagnosed malignant neoplasm in men in the developed countries. Although the progression of prostate cancer and the processes of invasion and metastasis by tumor cells are comparatively well understood, the genes involved in these processes are not fully determined. Therefore, a common area of research interest is the identification of novel molecules that are involved in these processes. In the present study, we have used in silico and experimental approaches to compare the expression of embryonal Fyn-associated substrate (EFS) between normal prostate and prostate cancer. We showed that EFS expression is remarkably downregulated in prostate cancer cells, compared to normal prostate cells. We also found that decreased expression of EFS in prostate cancer cells is due to DNA methylation. In addition, we showed that high EFS expression is important to suppress a malignant behavior of prostate cancer cells. Therefore, we suggest that EFS should be considered as a novel tumor suppressor gene in prostate cancer.

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Androgen regulated HN1 leads proteosomal degradation of androgen receptor (AR) and negatively influences AR mediated transactivation in prostate cells

Cited by 33 publications

References 38 publications

New transcriptional-based insights into the pathogenesis of desmoplastic small round cell tumors (DSRCTs)

New transcriptional-based insights into the pathogenesis of desmoplastic small round cell tumors (DSRCTs)

Androgen receptor phosphorylation: biological context and functional consequences

Decreased expression of EFS is correlated with the advanced prostate cancer

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