scholarly journals Epigenetic changes in fibroblasts drive cancer metabolism and differentiation

2019 ◽  
Vol 26 (12) ◽  
pp. R673-R688 ◽  
Author(s):  
Rajeev Mishra ◽  
Subhash Haldar ◽  
Surabhi Suchanti ◽  
Neil A Bhowmick
Keyword(s):  
Prostate Cancer ◽  
Cancer Progression ◽  
Cancer Metabolism ◽  
Promoter Hypermethylation ◽  
Ras Signaling ◽  
Androgen Receptor Signaling ◽  
Genomic Changes ◽  
Signaling Axis ◽  
Carcinoma Associated Fibroblasts ◽  
Methylation Patterns

Genomic changes that drive cancer initiation and progression contribute to the co-evolution of the adjacent stroma. The nature of the stromal reprogramming involves differential DNA methylation patterns and levels that change in response to the tumor and systemic therapeutic intervention. Epigenetic reprogramming in carcinoma-associated fibroblasts are robust biomarkers for cancer progression and have a transcriptional impact that support cancer epithelial progression in a paracrine manner. For prostate cancer, promoter hypermethylation and silencing of the RasGAP, RASAL3 that resulted in the activation of Ras signaling in carcinoma-associated fibroblasts. Stromal Ras activity initiated a process of macropinocytosis that provided prostate cancer epithelia with abundant glutamine for metabolic conversion to fuel its proliferation and a signal to transdifferentiate into a neuroendocrine phenotype. This epigenetic oncogenic metabolic/signaling axis seemed to be further potentiated by androgen receptor signaling antagonists and contributed to therapeutic resistance. Intervention of stromal signaling may complement conventional therapies targeting the cancer cell.

scholarly journals Interplay Between SOX9, Wnt/β-Catenin and Androgen Receptor Signaling in Castration-Resistant Prostate Cancer

2019 ◽  
Vol 20 (9) ◽  
pp. 2066 ◽  
Author(s):  
Namrata Khurana ◽  
Suresh C. Sikka
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Signaling Pathways ◽  
Critical Role ◽  
Castration Resistant Prostate Cancer ◽  
Form Complex ◽  
Androgen Receptor Signaling ◽  
Castration Resistant ◽  
Signaling Axis

Androgen receptor (AR) signaling plays a key role not only in the initiation of prostate cancer (PCa) but also in its transition to aggressive and invasive castration-resistant prostate cancer (CRPC). However, the crosstalk of AR with other signaling pathways contributes significantly to the emergence and growth of CRPC. Wnt/β-catenin signaling facilitates ductal morphogenesis in fetal prostate and its anomalous expression has been linked with PCa. β-catenin has also been reported to form complex with AR and thus augment AR signaling in PCa. The transcription factor SOX9 has been shown to be the driving force of aggressive and invasive PCa cells and regulate AR expression in PCa cells. Furthermore, SOX9 has also been shown to propel PCa by the reactivation of Wnt/β-catenin signaling. In this review, we discuss the critical role of SOX9/AR/Wnt/β-catenin signaling axis in the development and progression of CRPC. The phytochemicals like sulforaphane and curcumin that can concurrently target SOX9, AR and Wnt/β-catenin signaling pathways in PCa may thus be beneficial in the chemoprevention of PCa.

scholarly journals Androgen Receptor Signaling in Prostate Cancer Genomic Subtypes

Cancers ◽  
2021 ◽  
Vol 13 (13) ◽  
pp. 3272
Author(s):  
Lauren K. Jillson ◽  
Gabriel A. Yette ◽  
Teemu D. Laajala ◽  
Wayne D. Tilley ◽  
James C. Costello ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Targeted Therapies ◽  
Meta Analysis ◽  
Therapy Resistance ◽  
Androgen Receptor Signaling ◽  
Genomic Changes ◽  
Risk Patients ◽  
Important Pathway ◽  
Therapy Option

While many prostate cancer (PCa) cases remain indolent and treatable, others are aggressive and progress to the metastatic stage where there are limited curative therapies. Androgen receptor (AR) signaling remains an important pathway for proliferative and survival programs in PCa, making disruption of AR signaling a viable therapy option. However, most patients develop resistance to AR-targeted therapies or inherently never respond. The field has turned to PCa genomics to aid in stratifying high risk patients, and to better understand the mechanisms driving aggressive PCa and therapy resistance. While alterations to the AR gene itself occur at later stages, genomic changes at the primary stage can affect the AR axis and impact response to AR-directed therapies. Here, we review common genomic alterations in primary PCa and their influence on AR function and activity. Through a meta-analysis of multiple independent primary PCa databases, we also identified subtypes of significantly co-occurring alterations and examined their combinatorial effects on the AR axis. Further, we discussed the subsequent implications for response to AR-targeted therapies and other treatments. We identified multiple primary PCa genomic subtypes, and given their differing effects on AR activity, patient tumor genetics may be an important stratifying factor for AR therapy resistance.

scholarly journals FKBP51 Promotes Assembly of the Hsp90 Chaperone Complex and Regulates Androgen Receptor Signaling in Prostate Cancer Cells

2010 ◽  
Vol 30 (5) ◽  
pp. 1243-1253 ◽  
Author(s):  
Li Ni ◽  
Chun-Song Yang ◽  
Daniel Gioeli ◽  
Henry Frierson ◽  
David O. Toft ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cancer Cells ◽  
Cancer Progression ◽  
Feedback Loop ◽  
Critical Role ◽  
Prostate Cancer Cells ◽  
Androgen Receptor Signaling ◽  
Hsp90 Chaperone ◽  
Chaperone Complex ◽  
Androgen Binding

ABSTRACT Prostate cancer progression to the androgen-independent (AI) state involves acquisition of pathways that allow tumor growth under low-androgen conditions. We hypothesized that expression of molecular chaperones that modulate androgen binding to AR might be altered in prostate cancer and contribute to progression to the AI state. Here, we report that the Hsp90 cochaperone FKBP51 is upregulated in LAPC-4 AI tumors grown in castrated mice and describe a molecular mechanism by which FKBP51 regulates AR activity. Using recombinant proteins, we show that FKBP51 stimulates recruitment of the cochaperone p23 to the ATP-bound form of Hsp90, forming an FKBP51-Hsp90-p23 superchaperone complex. In cells, FKBP51 expression promotes superchaperone complex association with AR and increases the number of AR molecules that undergo androgen binding. FKBP51 stimulates androgen-dependent transcription and cell growth, and FKBP51 is part of a positive feedback loop that is regulated by AR and androgen. Finally, depleting FKBP51 levels by short hairpin RNA reduces the transcript levels of genes regulated by AR and androgen. Because the superchaperone complex plays a critical role in determining the ligand-binding competence and transcription function of AR, it provides an attractive target for inhibiting AR activity in prostate cancer cells.

scholarly journals Interplay between the androgen receptor signaling axis and microRNAs in prostate cancer

2019 ◽  
Vol 26 (5) ◽  
pp. R237-R257 ◽  
Author(s):  
Rayzel C Fernandes ◽  
Theresa E Hickey ◽  
Wayne D Tilley ◽  
Luke A Selth
Keyword(s):  
Gene Expression ◽  
Prostate Cancer ◽  
Transcription Factor ◽  
Androgen Receptor ◽  
Molecular Mechanisms ◽  
Clinical Applications ◽  
Cancer Growth ◽  
Androgen Receptor Signaling ◽  
Resistance To Therapy ◽  
Signaling Axis

The androgen receptor (AR) is a ligand-activated transcription factor that drives prostate cancer. Since therapies that target the AR are the mainstay treatment for men with metastatic disease, it is essential to understand the molecular mechanisms underlying oncogenic AR signaling in the prostate. miRNAs are small, non-coding regulators of gene expression that play a key role in prostate cancer and are increasingly recognized as targets or modulators of the AR signaling axis. In this review, we examine the regulation of AR signaling by miRNAs and vice versa and discuss how this interplay influences prostate cancer growth, metastasis and resistance to therapy. Finally, we explore the potential clinical applications of miRNAs implicated in the regulation of AR signaling in this prevalent hormone-driven disease.

scholarly journals BRD9 is a critical regulator of androgen receptor signaling and prostate cancer progression

2020 ◽  
pp. canres.1417.2020
Author(s):  
Aktan Alpsoy ◽  
Sagar M Utturkar ◽  
Benjamin C Carter ◽  
Alisha Dhiman ◽  
Sandra E Torregrosa-Allen ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Cancer Progression ◽  
Receptor Signaling ◽  
Prostate Cancer Progression ◽  
Androgen Receptor Signaling

PROMOTER HYPERMETHYLATION IN CIRCULATING BLOOD CELLS IDENTIFIES PROSTATE CANCER PROGRESSION

2008 ◽  
Vol 7 (3) ◽  
pp. 254
Author(s):  
M. Roupret ◽  
V. Hupertan ◽  
W.F. Catto ◽  
D.R. Yates ◽  
I. Rehman ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cancer Progression ◽  
Blood Cells ◽  
Promoter Hypermethylation ◽  
Prostate Cancer Progression
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