scholarly journals ACK1–AR and AR–HOXB13 signaling axes: epigenetic regulation of lethal prostate cancers

NAR Cancer ◽  
2020 ◽  
Vol 2 (3) ◽  
Author(s):  
Eric H Kim ◽  
Dengfeng Cao ◽  
Nupam P Mahajan ◽  
Gerald L Andriole ◽  
Kiran Mahajan
Keyword(s):  
Chromatin Remodeling ◽  
Target Genes ◽  
Kinase Inhibitor ◽  
Histone H4 ◽  
Castration Resistant ◽  
Survival Pathways ◽  
Small Molecule Kinase Inhibitor ◽  
Domain Protein ◽  
Prostate Cancers ◽  
Androgen Depletion

Abstract The androgen receptor (AR) is a critical transcription factor in prostate cancer (PC) pathogenesis. Its activity in malignant cells is dependent on interactions with a diverse set of co-regulators. These interactions fluctuate depending on androgen availability. For example, the androgen depletion increases the dependence of castration-resistant PCs (CRPCs) on the ACK1 and HOXB13 cell survival pathways. Activated ACK1, an oncogenic tyrosine kinase, phosphorylates cytosolic and nuclear proteins, thereby avoiding the inhibitory growth consequences of androgen depletion. Notably, ACK1-mediated phosphorylation of histone H4, which leads to epigenetic upregulation of AR expression, has emerged as a critical mechanism of CRPC resistance to anti-androgens. This resistance can be targeted using the ACK1-selective small-molecule kinase inhibitor (R)-9b. CRPCs also deploy the bromodomain and extra-terminal domain protein BRD4 to epigenetically increase HOXB13 gene expression, which in turn activates the MYC target genes AURKA/AURKB. HOXB13 also facilitates ligand-independent recruitment of the AR splice variant AR-V7 to chromatin, compensating for the loss of the chromatin remodeling protein, CHD1, and restricting expression of the mitosis control gene HSPB8. These studies highlight the crosstalk between AR–ACK1 and AR–HOXB13 pathways as key mediators of CRPC recurrence.

scholarly journals Locus-Wide Chromatin Remodeling and Enhanced Androgen Receptor-Mediated Transcription in Recurrent Prostate Tumor Cells

2006 ◽  
Vol 26 (19) ◽  
pp. 7331-7341 ◽  
Author(s):  
Li Jia ◽  
Howard C. Shen ◽  
Marcus Wantroba ◽  
Omar Khalid ◽  
Gangning Liang ◽  
...  
Keyword(s):  
Gene Expression ◽  
Androgen Receptor ◽  
Histone Acetylation ◽  
Chromatin Remodeling ◽  
Target Genes ◽  
Specific Antigen ◽  
Entire Body ◽  
Prostate Cancers ◽  
Prostate Tumor Cells ◽  
Androgen Independent

ABSTRACT Prostate cancers (PCas) become resistant to hormone withdrawal through increased androgen receptor (AR) signaling. Here we show increased AR-mediated transcription efficiency in PCa cells that have acquired the ability to grow in low concentrations of androgen. Compared to androgen-dependent PCa cells, these cells showed increased activity of transiently transfected reporters and increased mRNA synthesis relative to levels of AR occupancy of the prostate-specific antigen (PSA) gene. The locus also displayed up to 10-fold-higher levels of histone H3-K9/K14 acetylation and H3-K4 methylation across the entire body of the gene. Although similar increased mRNA expression and locus-wide histone acetylation were also observed at another kallikrein locus (KLK2), at a third AR target locus (TMPRSS2) increased gene expression and locus-wide histone acetylation were not seen in the absence of ligand. Androgen-independent PCa cells have thus evolved three distinctive alterations in AR-mediated transcription. First, increased RNA polymerase initiation and processivity contributed to increased gene expression. Second, AR signaling was more sensitive to ligand. Third, locus-wide chromatin remodeling conducive to the increased gene expression in the absence of ligand was apparent and depended on sustained AR activity. Therefore, increased AR ligand sensitivity as well as locus-specific chromatin alterations contribute to basal gene expression of a subpopulation of specific AR target genes in androgen-independent PCa cells. These features contribute to the androgen-independent phenotype of these cells.

scholarly journals ATRT-03. IDENTIFICATION OF microRNA-BASED PROGNOSTIC BIOMARKERS AND CANDIDATE THERAPEUTIC AGENTS FOR ATYPICAL TERATOID/RHABDOID TUMOR

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii275-iii276
Author(s):  
Yang Zhang ◽  
Jianguo Xu
Keyword(s):  
Target Genes ◽  
Kinase Inhibitor ◽  
Therapeutic Agents ◽  
Rhabdoid Tumor ◽  
Janus Kinase ◽  
Prognostic Biomarkers ◽  
Atypical Teratoid Rhabdoid Tumor ◽  
Overlapping Genes ◽  
Hub Genes ◽  
Atypical Teratoid

Abstract BACKGROUND MicroRNA (miRNA) has been found to be involved in development of many malignant pediatric brain tumors, including atypical teratoid/rhabdoid tumor (AT/RT) that is highly aggressive and carries a dismal prognosis. The current study investigated the potential value of miRNAs and pivotal genes associated with AT/RT using bioinformatics analysis, aiming to identify new prognostic biomarkers and candidate drugs for AT/RT patients. METHODS Differentially expressed miRNAs (DEMs) and genes (DEGs) between AT/RT and normal control samples were obtained from GEO database. The target genes of DEMs were predicted via TargetScanHuman7.2 and miRDB, and then intersected with DEGs. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses of overlapping genes were conducted, followed by construction of protein-protein interaction network. Hub genes were determined by Cytoscape software, and their prognostic values were evaluated using Kaplan-Meier analysis. Connectivity Map database was used to identify latent therapeutic agents. RESULTS A total of 11 DEMs (hsa-miR-1224-5p, hsa-miR-128-3p, hsa-miR-17-5p, hsa-miR-18b-5p, hsa-miR-29c-5p, hsa-miR-329-3p, hsa-miR-379-5p, hsa-miR-433-3p, hsa-miR-488-5p, hsa-miR-656-3p and hsa-miR-885-5p) were screened. By intersecting 3275 predicted target genes and 925 DEGs, we finally identified 226 overlapping genes that were enriched in pathways in cancer and MAPK signaling pathway. Four hub genes (GRIA2, NRXN1, SLC6A1 and SYT1) were significantly associated with the overall survival of AT/RT patients. Candidate drugs included histone deacetylase inhibitor (givinostat), DNA synthesis inhibitor (floxuridine), cyclin-dependent kinase inhibitor (purvalanol) and janus kinase inhibitor (lestaurtinib). CONCLUSION In summary, this study systematically analyzed AT/RT-related miRNAs and pivotal genes to provide novel prognostic biomarkers and potential therapeutic agents.

scholarly journals Activation of the p11/SMARCA3/Neurensin-2 pathway in parvalbumin interneurons mediates the response to chronic antidepressants

2021 ◽  
Author(s):  
Gali Umschweif ◽  
Lucian Medrihan ◽  
Kathryn A. McCabe ◽  
Yotam Sagi ◽  
Paul Greengard
Keyword(s):  
Chromatin Remodeling ◽  
Behavioral Response ◽  
Hippocampal Neurons ◽  
Selective Serotonin Reuptake Inhibitors ◽  
Chronic Treatment ◽  
Target Genes ◽  
Delayed Response ◽  
Dynamic Changes ◽  
Parvalbumin Interneurons ◽  
Transcriptional Changes

AbstractThe delayed behavioral response to chronic antidepressants depends on dynamic changes in the hippocampus. It was suggested that the antidepressant protein p11 and the chromatin remodeling factor SMARCA3 mediate this delayed response by inducing transcriptional changes in hippocampal neurons. However, what target genes are regulated by the p11/SMARCA3 complex to mediate the behavioral response to antidepressants, and what cell type mediates these molecular changes remain unknown. Here we report that the p11/SMARCA3 complex represses Neurensin-2 transcription in hippocampal parvalbumin-expressing interneurons after chronic treatment with Selective Serotonin Reuptake Inhibitors (SSRI). The behavioral response to antidepressants requires upregulation of p11, accumulation of SMARCA3 in the cell nucleus, and a consequent repression of Neurensin-2 transcription in these interneurons. We elucidate a functional role for p11/SMARCA3/Neurensin-2 pathway in regulating AMPA-receptor signaling in parvalbumin-expressing interneurons, a function that is enhanced by chronic treatment with SSRIs. These results link SSRIs to dynamic glutamatergic changes and implicate p11/SMARCA3/Neurensin-2 pathway in the development of more specific and efficient therapeutic strategies for neuropsychiatric disorders.

Activation of an alfalfa cyclin-dependent kinase inhibitor by calmodulin-like domain protein kinase

2006 ◽  
Vol 46 (1) ◽  
pp. 111-123 ◽  
Author(s):  
Aladár Pettkó-Szandtner ◽  
Tamás Mészáros ◽  
Gábor V. Horváth ◽  
László Bakó ◽  
Éva Csordás-Tóth ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Kinase Inhibitor ◽  
Cyclin Dependent Kinase ◽  
Cyclin Dependent Kinase Inhibitor ◽  
Domain Protein

scholarly journals Maintenance of Open Chromatin and Selective Genomic Occupancy at the Cell Cycle-Regulated Histone H4 Promoter during Differentiation of HL-60 Promyelocytic Leukemia Cells

2003 ◽  
Vol 23 (4) ◽  
pp. 1460-1469 ◽  
Author(s):  
Hayk Hovhannisyan ◽  
Brian Cho ◽  
Partha Mitra ◽  
Martin Montecino ◽  
Gary S. Stein ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Kinase Inhibitor ◽  
Restriction Enzymes ◽  
Dnase I ◽  
Promyelocytic Leukemia ◽  
Micrococcal Nuclease ◽  
Leukemia Cells ◽  
N Gene ◽  
Open Chromatin ◽  
Histone H4

ABSTRACT During the shutdown of proliferation and onset of differentiation of HL-60 promyelocytic leukemia cells, expression of the cell cycle-dependent histone genes is downregulated at the level of transcription. To address the mechanism by which this regulation occurs, we examined the chromatin structure of the histone H4/n (FO108, H4FN) gene locus. Micrococcal nuclease, DNase I, and restriction enzymes show similar cleavage sites and levels of sensitivity at the H4/n locus in both proliferating and differentiated HL-60 cells. In contrast, differentiation-related activation of the cyclin-dependent kinase inhibitor p21cip1/WAF1 gene is accompanied by increased nuclease hypersensitivity. Chromatin immunoprecipitation assays of the H4/n gene reveal that acetylated histones H3 and H4 are maintained at the same levels in proliferating and postproliferative cells. Thus, the chromatin of the H4/n locus remains in an open state even after transcription ceases. Using ligation-mediated PCR to visualize genomic DNase I footprints at single-nucleotide resolution, we find that protein occupancy at the site II cell cycle element is selectively diminished in differentiated cells while the site I element remains occupied. Decreased occupancy of site II is reflected by loss of the site II binding protein HiNF-P. We conclude that H4 gene transcription during differentiation is downregulated by modulating protein interaction at the site II cell cycle element and that retention of an open chromatin conformation may be associated with site I occupancy.

The trithorax group gene osa encodes an ARID-domain protein that genetically interacts with the brahma chromatin-remodeling factor to regulate transcription

Development ◽  
1999 ◽  
Vol 126 (4) ◽  
pp. 733-742 ◽  
Author(s):  
M. Vazquez ◽  
L. Moore ◽  
J.A. Kennison
Keyword(s):  
Gene Regulation ◽  
Chromatin Remodeling ◽  
Homeotic Gene ◽  
Dna Binding Domain ◽  
Atpase Subunit ◽  
Trithorax Group ◽  
Chromatin Remodeling Complex ◽  
P2 Promoter ◽  
Domain Protein ◽  
Arid Domain

The trithorax group gene brahma (brm) encodes the ATPase subunit of a chromatin-remodeling complex involved in homeotic gene regulation. We report here that brm interacts with another trithorax group gene, osa, to regulate the expression of the Antennapedia P2 promoter. Regulation of Antennapedia by BRM and OSA proteins requires sequences 5′ to the P2 promoter. Loss of maternal osa function causes severe segmentation defects, indicating that the function of osa is not limited to homeotic gene regulation. The OSA protein contains an ARID domain, a DNA-binding domain also present in the yeast SWI1 and Drosophila DRI proteins. We propose that the OSA protein may target the BRM complex to Antennapedia and other regulated genes.

Sex Hormones and Prostate Cancer

2020 ◽  
Vol 71 (1) ◽  
pp. 33-45 ◽  
Author(s):  
Richard J. Auchus ◽  
Nima Sharifi
Keyword(s):  
Prostate Cancer ◽  
Metastatic Prostate Cancer ◽  
Current Treatment ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistant ◽  
History Of ◽  
Prostate Cancer Research ◽  
Prostate Cancers ◽  
Androgen Independent ◽  
Transition Studies

The prostate is an androgen-dependent organ that develops only in male mammals. Prostate cancer is the most common nonskin malignancy in men and the second leading cause of cancer deaths. Metastatic prostate cancer initially retains its androgen dependence, and androgen-deprivation therapy often leads to disease control; however, the cancer inevitably progresses despite treatment as castration-resistant prostate cancer, the lethal form of the disease. Although it was assumed that the cancer became androgen independent during this transition, studies over the last two decades have shown that these tumors evade treatment via mechanisms that augment acquisition of androgens from circulating precursors, increase sensitivity to androgens and androgen precursors, bypass the androgen receptor, or a combination of these mechanisms. This review summarizes the history of prostate cancer research leading to the contemporary view of androgen dependence for prostate cancers and the current treatment approaches based on this modern paradigm.

scholarly journals The Morpho-Functional Parameters of Rat Pituitary Hormone Producing Cells After Genistein Treatment

2018 ◽  
Vol 41 (1) ◽  
pp. 5-19 ◽  
Author(s):  
Svetlana Trifunović ◽  
Verica Milošević
Keyword(s):  
Replacement Therapy ◽  
Estrogen Replacement Therapy ◽  
Target Genes ◽  
Kinase Inhibitor ◽  
Endocrine System ◽  
The Body ◽  
Pituitary Hormone ◽  
Estrogen Replacement ◽  
Genistein Treatment ◽  
Rat Pituitary

AbstractPhytoestrogens are a diverse group of steroid–like compounds that occur naturally in many plants. There are various types of phytoestrogens, including the best-researched isoflavones which are commonly found in soy. The consumption of soy products has many health benefits, including protection against breast cancer, prostate cancer, menopausal symptoms, heart disease and osteoporosis. In contrast, use of hormonally active compounds-isoflavones may unfortunately interfere with the endocrine system and can have far-reaching consequences. Genistein, the most abundant soy-bean derived isoflavone, possesses a ring system similar to estrogens and acts through an estrogen receptor (ER)-mediated mechanism, by increasing or decreasing the transcription of ER-dependent target genes. Also, genistein can act on cells through ER non-dependent mechanisms, such as tyrosine kinase inhibitor. The neuroendocrine systems are responsible for the control of homeostatic processes in the body, including reproduction, growth, metabolism and energy balance, and stress responsiveness. It is well known, that estrogen is important for development of the neuroendocrine system in both sexes. At the pituitary level, estrogen is known to affect the regulation of all hormone producing (HP) cells, by direct and/or indirect mechanisms. Due to structural and functional resemblance to estrogen, the question may arise of whether and how genistein affects the morphofunctional features of pituitary HP cells. This review deals with the consequences of genistein’s effects on morphological, stereological and hormonal features of HP cells within the anterior pituitary gland. Transparency on this issue is needed because isoflavones are presently highly consumed. Inter alia, genistein as well as other isoflavones, are present in various dietary supplements and generally promoted as an accepted alternative to estrogen replacement therapy. Potential isoflavone biomedical exploitation is not only limited to estrogen replacement therapy, so it should be treated in a wider context of different ageing symptoms remediation.

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