scholarly journals CK2 Pro-Survival Role in Prostate Cancer Is Mediated via Maintenance and Promotion of Androgen Receptor and NFκB p65 Expression

2019 ◽  
Vol 12 (2) ◽  
pp. 89
Author(s):  
Janeen H. Trembley ◽  
Betsy T. Kren ◽  
Md. J. Abedin ◽  
Daniel P. Shaughnessy ◽  
Yingming Li ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Inhibitory Effect ◽  
Strongly Correlated ◽  
Protein Levels ◽  
Small Molecule Inhibition ◽  
Prostate Cells ◽  
Cell Death Response ◽  
Stress Signals ◽  
Castrate Resistant

The prosurvival protein kinase CK2, androgen receptor (AR), and nuclear factor kappa B (NFκB) interact in the function of prostate cells, and there is evidence of crosstalk between these signals in the pathobiology of prostate cancer (PCa). As CK2 is elevated in PCa, and AR and NFκB are involved in the development and progression of prostate cancer, we investigated their interaction in benign and malignant prostate cells in the presence of altered CK2 expression. Our results show that elevation of CK2 levels caused increased levels of AR and NFκB p65 in prostate cells of different phenotypes. Analysis of TCGA PCa data indicated that AR and CK2α RNA expression are strongly correlated. Small molecule inhibition or molecular down-regulation of CK2 caused reduction in AR mRNA expression and protein levels in PCa cells and in orthotopic xenograft tumors by various pathways. Among these, regulation of AR protein stability plays a unifying role in CK2 maintenance of AR protein levels. Our results show induction of various endoplasmic reticulum stress signals after CK2 inhibition, which may play a role in the PCa cell death response. Of note, CK2 inhibition caused loss of cell viability in both parental and enzalutamide-resistant castrate-resistant PCa cells. The present work elucidates the specific link of CK2 to the pathogenesis of PCa in association with AR and NFκB expression; further, the observation that inhibition of CK2 can exert a growth inhibitory effect on therapy-resistant PCa cells emphasizes the potential utility of CK2 inhibition in patients who are on enzalutamide treatment for advanced cancer.

scholarly journals Functional mapping of androgen receptor enhancer activity

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Chia-Chi Flora Huang ◽  
Shreyas Lingadahalli ◽  
Tunc Morova ◽  
Dogancan Ozturan ◽  
Eugene Hu ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Binding Sites ◽  
Gene Promoters ◽  
Strongly Correlated ◽  
Enhancer Activity ◽  
Drive Gene Expression ◽  
In Vitro Cell Lines ◽  
Drive Gene

Abstract Background Androgen receptor (AR) is critical to the initiation, growth, and progression of prostate cancer. Once activated, the AR binds to cis-regulatory enhancer elements on DNA that drive gene expression. Yet, there are 10–100× more binding sites than differentially expressed genes. It is unclear how or if these excess binding sites impact gene transcription. Results To characterize the regulatory logic of AR-mediated transcription, we generated a locus-specific map of enhancer activity by functionally testing all common clinical AR binding sites with Self-Transcribing Active Regulatory Regions sequencing (STARRseq). Only 7% of AR binding sites displayed androgen-dependent enhancer activity. Instead, the vast majority of AR binding sites were either inactive or constitutively active enhancers. These annotations strongly correlated with enhancer-associated features of both in vitro cell lines and clinical prostate cancer samples. Evaluating the effect of each enhancer class on transcription, we found that AR-regulated enhancers frequently interact with promoters and form central chromosomal loops that are required for transcription. Somatic mutations of these critical AR-regulated enhancers often impact enhancer activity. Conclusions Using a functional map of AR enhancer activity, we demonstrated that AR-regulated enhancers act as a regulatory hub that increases interactions with other AR binding sites and gene promoters.

scholarly journals Androgen receptor moonlighting in the prostate cancer microenvironment

2018 ◽  
Vol 25 (6) ◽  
pp. R331-R349 ◽  
Author(s):  
B Cioni ◽  
W Zwart ◽  
A M Bergman
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Cancer Progression ◽  
Stromal Cells ◽  
Normal Development ◽  
Protective Role ◽  
Biological Action ◽  
Prostate Cells ◽  
Classical Function ◽  
Biological Literature

Androgen receptor (AR) signaling is vital for the normal development of the prostate and is critically involved in prostate cancer (PCa). AR is not only found in epithelial prostate cells but is also expressed in various cells in the PCa-associated stroma, which constitute the tumor microenvironment (TME). In the TME, AR is expressed in fibroblasts, macrophages, lymphocytes and neutrophils. AR expression in the TME was shown to be decreased in higher-grade and metastatic PCa, suggesting that stromal AR plays a protective role against PCa progression. With that, the functionality of AR in stromal cells appears to deviate from the receptor’s classical function as described in PCa cells. However, the biological action of AR in these cells and its effect on cancer progression remains to be fully understood. Here, we systematically review the pathological, genomic and biological literature on AR actions in various subsets of prostate stromal cells and aim to better understand the consequences of AR signaling in the TME in relation to PCa development and progression.

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