scholarly journals Chromatin-directed proteomics-identified network of endogenous androgen receptor in prostate cancer cells

Oncogene ◽  
2021 ◽  
Author(s):  
Kaisa-Mari Launonen ◽  
Ville Paakinaho ◽  
Gianluca Sigismondo ◽  
Marjo Malinen ◽  
Reijo Sironen ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Target Genes ◽  
Epithelial Mesenchymal Transition ◽  
Protein A ◽  
Chorioallantoic Membrane ◽  
Chromatin Accessibility ◽  
Castration Resistant Prostate Cancer ◽  
Novel Therapy ◽  
Mesenchymal Transition

AbstractTreatment of prostate cancer confronts resistance to androgen receptor (AR)-targeted therapies. AR-associated coregulators and chromatin proteins hold a great potential for novel therapy targets. Here, we employed a powerful chromatin-directed proteomics approach termed ChIP-SICAP to uncover the composition of chromatin protein network, the chromatome, around endogenous AR in castration resistant prostate cancer (CRPC) cells. In addition to several expected AR coregulators, the chromatome contained many nuclear proteins not previously associated with the AR. In the context of androgen signaling in CRPC cells, we further investigated the role of a known AR-associated protein, a chromatin remodeler SMARCA4 and that of SIM2, a transcription factor without a previous association with AR. To understand their role in chromatin accessibility and AR target gene expression, we integrated data from ChIP-seq, RNA-seq, ATAC-seq and functional experiments. Despite the wide co-occurrence of SMARCA4 and AR on chromatin, depletion of SMARCA4 influenced chromatin accessibility and expression of a restricted set of AR target genes, especially those involved in cell morphogenetic changes in epithelial-mesenchymal transition. The depletion also inhibited the CRPC cell growth, validating SMARCA4’s functional role in CRPC cells. Although silencing of SIM2 reduced chromatin accessibility similarly, it affected the expression of a much larger group of androgen-regulated genes, including those involved in cellular responses to external stimuli and steroid hormone stimulus. The silencing also reduced proliferation of CRPC cells and tumor size in chick embryo chorioallantoic membrane assay, further emphasizing the importance of SIM2 in CRPC cells and pointing to the functional relevance of this potential prostate cancer biomarker in CRPC cells. Overall, the chromatome of AR identified in this work is an important resource for the field focusing on this important drug target.

scholarly journals Isoform specific activities of androgen receptor and its splice variants in prostate cancer cells

Endocrinology ◽  
2020 ◽  
Author(s):  
Harika Nagandla ◽  
Matthew J Robertson ◽  
Vasanta Putluri ◽  
Nagireddy Putluri ◽  
Cristian Coarfa ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Target Gene ◽  
Target Genes ◽  
Splice Variants ◽  
Clinical Samples ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistant ◽  
Specific Activities ◽  
Lncap Prostate Cancer Cell

Abstract Androgen receptor (AR) signaling continues to drive castration resistant prostate cancer (CRPC) in spite of androgen deprivation therapy (ADT). Constitutively active shorter variants of AR, lacking the ligand binding domain, are frequently expressed in CRPC and have emerged as a potential mechanism for prostate cancer to escape ADT. ARv7 and AR v567es are two of the most commonly detected variants of AR in clinical samples of advanced, metastatic prostate cancer. It is not clear if variants of AR merely act as weaker substitutes for AR or can mediate unique isoform specific activities different from AR. In this study, we employed LNCaP prostate cancer cell lines with inducible expression of ARv7 or AR v567es to delineate similarities and differences in transcriptomics, metabolomics and lipidomics resulting from the activation of AR, ARv7 or AR v567es. While the majority of target genes were similarly regulated by the action of all three isoforms, we found a clear difference in transcriptomic activities of AR versus the variants, and a few differences between ARv7 and AR v567es. Some of the target gene regulation by AR isoforms was similar in the VCaP background as well. Differences in downstream activities of AR isoforms were also evident from comparison of the metabolome and lipidome in an LNCaP model. Overall our study implies that shorter variants of AR are capable of mediating unique downstream activities different from AR and some of these are isoform specific.

Dual targeting of EZH2 and androgen receptor as a novel therapy for castration-resistant prostate cancer

2020 ◽  
Vol 404 ◽  
pp. 115200 ◽  
Author(s):  
Eswar Shankar ◽  
Daniel Franco ◽  
Omair Iqbal ◽  
Stephen Moreton ◽  
Rajnee Kanwal ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Castration Resistant Prostate Cancer ◽  
Novel Therapy ◽  
Castration Resistant ◽  
Dual Targeting

scholarly journals Activation of GPR56, a novel adhesion GPCR, is necessary for nuclear androgen receptor signaling in prostate cells

2019 ◽  
Author(s):  
Julie Pratibha Singh ◽  
Manisha Dagar ◽  
Gunjan Dagar ◽  
Sudhir Rawal ◽  
Ravi Datta Sharma ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Intracellular Signaling ◽  
Target Genes ◽  
Nuclear Translocation ◽  
Prostate Tumor ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistant ◽  
Pka Pathway ◽  
Adhesion Gpcr

AbstractThe androgen receptor (AR) is activated in patients with castration resistant prostate cancer (CRPC) despite low circulating levels of androgen, suggesting that intracellular signaling pathways and non-androgenic factors may contribute to AR activation. Many G-protein coupled receptors (GPCR) and their ligands are also activated in these cells indicating a role for these in CRPC. Although a cross talk has been suggested between the two pathways, yet, the identity of GPCRs which may play a role in androgen signaling, is not established yet. We demonstrate that adhesion GPCR 205, also known as GPR56, can be activated by androgens to stimulate the Rho signaling pathway, a pathway that plays an important role in prostate tumor cell metastasis. Testosterone stimulation of GPR56 also activates the cAMP/ Protein kinase A (PKA) pathway, that is necessary for AR signaling. Knocking down the expression of GPR56 using siRNA, disrupts nuclear translocation of AR and transcription of prototypic AR target genes such as PSA. GPR56 expression is higher in all prostate tumor samples tested and cells expressing GPR56 exhibit increased proliferation. These findings provide new insights about androgen signaling and identify GPR56 as a possible therapeutic target in advanced prostate cancer patients.

scholarly journals Histone lysine demethylase KDM4B regulates the alternative splicing of the androgen receptor in response to androgen deprivation

2019 ◽  
Author(s):  
Lingling Duan ◽  
Zhenhua Chen ◽  
Jun Lu ◽  
Yanping Liang ◽  
Ming Wang ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Alternative Splicing ◽  
Chromatin Accessibility ◽  
Splicing Factor ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistance ◽  
Cryptic Exon ◽  
Genome Wide ◽  
Lysine Demethylase

Abstract Alternative splicing is emerging as an oncogenic mechanism. In prostate cancer, generation of constitutively active forms of androgen receptor (AR) variants including AR-V7 plays an important role in progression of castration-resistant prostate cancer (CRPC). AR-V7 is generated by alternative splicing that results in inclusion of cryptic exon CE3 and translation of truncated AR protein that lacks the ligand binding domain. Whether AR-V7 can be a driver for CRPC remains controversial as the oncogenic mechanism of AR-V7 activation remains elusive. Here, we found that KDM4B promotes AR-V7 and identified a novel regulatory mechanism. KDM4B is phosphorylated by protein kinase A under conditions that promote castration-resistance, eliciting its binding to the splicing factor SF3B3. KDM4B binds RNA specifically near the 5′-CE3, upregulates the chromatin accessibility, and couples the spliceosome to the chromatin. Our data suggest that KDM4B can function as a signal responsive trans-acting splicing factor and scaffold that recruits and stabilizes the spliceosome near the alternative exon, thus promoting its inclusion. Genome-wide profiling of KDM4B-regulated genes also identified additional alternative splicing events implicated in tumorigenesis. Our study defines KDM4B-regulated alternative splicing as a pivotal mechanism for generating AR-V7 and a contributing factor for CRPC, providing insight for mechanistic targeting of CRPC.

scholarly journals Nerve Growth Factor Induces Proliferation and Aggressiveness in Prostate Cancer Cells

Cancers ◽  
2019 ◽  
Vol 11 (6) ◽  
pp. 784 ◽  
Author(s):  
Marzia Di Donato ◽  
Gustavo Cernera ◽  
Antimo Migliaccio ◽  
Gabriella Castoria
Keyword(s):  
Prostate Cancer ◽  
Nerve Growth Factor ◽  
Growth Factor ◽  
Epithelial Mesenchymal Transition ◽  
Tyrosine Kinase Receptor ◽  
Primary Therapy ◽  
Castration Resistant Prostate Cancer ◽  
Antitumor Effects ◽  
Nerve Growth ◽  
Mesenchymal Transition

Resistance to hormone therapy and disease progression is the major challenge in clinical management of prostate cancer (PC). Drugs currently used in PC therapy initially show a potent antitumor effects, but PC gradually develops resistance, relapses and spreads. Most patients who fail primary therapy and have recurrences eventually develop castration-resistant prostate cancer (CRPC), which is almost incurable. The nerve growth factor (NGF) acts on a variety of non-neuronal cells by activating the NGF tyrosine-kinase receptor, tropomyosin receptor kinase A (TrkA). NGF signaling is deregulated in PC. In androgen-dependent PC cells, TrkA mediates the proliferative action of NGF through its crosstalk with the androgen receptor (AR). Epithelial PC cells, however, acquire the ability to express NGF and TrkA, as the disease progresses, indicating a role for NGF/TrkA axis in PC progression and androgen-resistance. We here report that once activated by NGF, TrkA mediates proliferation, invasiveness and epithelial-mesenchymal transition (EMT) in various CRPC cells. NGF promotes organoid growth in 3D models of CRPC cells, and specific inhibition of TrkA impairs all these responses. Thus TrkA represents a new biomarker to target in CRPC.

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