The epigenetic and transcriptional landscape of neuroendocrine prostate cancer

Davies, Alastair; Zoubeidi, Amina; Selth, Luke A.

doi:10.1530/erc-19-0420

Cited by 62 publications

(77 citation statements)

References 132 publications

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“…The study pointed out, however, that among the 26% of the tumors without obvious molecular aberration there was evidence of DNA hypermethylation and mutations in epigenetic enzymes KDM6A and KMT2D [122]. Targeting the epigenetic landscape of PCa may help liberating this immune suppressive environment (see below), as illustrated by the influence of the methylatransferase EZH2, which inhibits T-lymphocyte chemoatractants (CXCL9 and CXCL10) and antigen presentation, thereby contributing to the "cold" microenvironment in CRPC with neuroendocrine differentiation [123].…”

Section: The Connection Between Genetic Epigenetic and Immune Landscmentioning

confidence: 99%

Targeting the Immune system and Epigenetic Landscape of Urological Tumors

Lobo

Jerónimo

Henrique

2020

IJMS

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In the last years, we have witnessed remarkable advances in targeted therapies for cancer patients. There is a growing effort to either replace or reduce the dose of unspecific, systemic (chemo)therapies, given the associated short- and long-term side effects, by introducing more specific targeted therapies as single or combination agents. Due to the well-known implications of the immune system and epigenetic landscape in modulating cancer development, both have been explored as potential targets in several malignancies, including those affecting the genitourinary tract. As the immune system function is also epigenetically regulated, there is rationale for combining both strategies. However, this is still rather underexplored, namely in urological tumors. We aim to briefly review the use of immune therapies in prostate, kidney, bladder, and testicular cancer, and further describe studies providing supporting evidence on their combination with epigenetic-based therapies.

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Section: The Connection Between Genetic Epigenetic and Immune Landscmentioning

confidence: 99%

Targeting the Immune system and Epigenetic Landscape of Urological Tumors

Lobo

Jerónimo

Henrique

2020

IJMS

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“…(iii) Activation of NE transcription factors e.g. ASCL1 and BRN2 that determine the commitment to a NE lineage ( 105 – 108 ). Among many other factors, EZH2 stands out to regulate NEPC-specific gene expression through epigenetic machinery ( 105 ).…”

Section: Metabolic Plasticity In Relation To Anti-ar Therapy and The mentioning

confidence: 99%

“…ASCL1 and BRN2 that determine the commitment to a NE lineage ( 105 – 108 ). Among many other factors, EZH2 stands out to regulate NEPC-specific gene expression through epigenetic machinery ( 105 ). Importantly, N-MYC forms a transcription repressor complex with EZH2 to repress AR transcription program ( 109 ).…”

Section: Metabolic Plasticity In Relation To Anti-ar Therapy and The mentioning

confidence: 99%

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Androgen Receptor Signaling and Metabolic and Cellular Plasticity During Progression to Castration Resistant Prostate Cancer

Sprenger

Plymate

2020

Front. Oncol.

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Metabolic reprogramming is associated with re/activation and antagonism of androgen receptor (AR) signaling that drives prostate cancer (PCa) progression to castration resistance, respectively. In particular, AR signaling influences the fates of citrate that uniquely characterizes normal and malignant prostatic metabolism (i.e., mitochondrial export and extracellular secretion in normal prostate, mitochondrial retention and oxidation to support oxidative phenotype of primary PCa, and extra-mitochondrial interconversion into acetyl-CoA for fatty acid synthesis and epigenetics in the advanced PCa). The emergence of castration-resistant PCa (CRPC) involves reactivation of AR signaling, which is then further targeted by androgen synthesis inhibitors (abiraterone) and AR-ligand inhibitors (enzalutamide, apalutamide, and daroglutamide). However, based on AR dependency, two distinct metabolic and cellular adaptations contribute to development of resistance to these agents and progression to aggressive and lethal disease, with the tumor ultimately becoming highly glycolytic and with imaging by a tracer of tumor energetics, 18 F-fluorodoxyglucose ( 18 F-FDG). Another major resistance mechanism involves a lineage alteration into AR-indifferent carcinoma such a neuroendocrine which is diagnostically characterized by robust 18 F-FDG uptake and loss of AR signaling. PCa is also characterized by metabolic alterations such as fatty acid and polyamine metabolism depending on AR signaling. In some cases, AR targeting induces rather than suppresses these alterations in cellular metabolism and energetics, which can be explored as therapeutic targets in lethal CRPC.

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“…Histone modifications, DNA methylation, and miRNAs have been shown as epigenetic modifications that play crucial roles in PCa growth and metastasis [37][38][39][40] . These epigenetic changes have a well-established role in regulating cellular plasticity in NEPC [41] . DNA methylation is a key epigenetic modification that affects transcription and development [42] .…”

Section: Nepc: Molecular Features and Epigeneticsmentioning

confidence: 99%

MicroRNAs in treatment-induced neuroendocrine differentiation in prostate cancer

Akoto¹,

Bhagirath²,

Saini³

2020

CDR

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Prostate cancer is a condition commonly associated with men worldwide. Androgen deprivation therapy remains one of the targeted therapies. However, after some years, there is biochemical recurrence and metastatic progression into castration-resistant prostate cancer (CRPC). CRPC cases are treated with second-line androgen deprivation therapy, after which, these CRPCs transdifferentiate to form neuroendocrine prostate cancer (NEPC), a highly aggressive variant of CRPC. NEPC arises via a reversible transdifferentiation process, known as neuroendocrine differentiation (NED), which is associated with altered expression of lineage markers such as decreased expression of androgen receptor and increased expression of neuroendocrine lineage markers including enolase 2, chromogranin A and synaptophysin. The etiological factors and molecular basis for NED are poorly understood, contributing to a lack of adequate molecular biomarkers for its diagnosis and therapy. Therefore, there is a need to fully understand the underlying molecular basis for this cancer. Recent studies have shown that microRNAs (miRNAs) play a key epigenetic role in driving therapy-induced NED in prostate cancer. In this review, we briefly describe the role of miRNAs in prostate cancer and CRPCs, discuss some key players in NEPCs and elaborate on miRNA dysregulation as a key epigenetic process that accompanies therapy-induced NED in metastatic CRPC. This understanding will contribute to better clinical management of the disease.

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The epigenetic and transcriptional landscape of neuroendocrine prostate cancer

Cited by 62 publications

References 132 publications

Targeting the Immune system and Epigenetic Landscape of Urological Tumors

Targeting the Immune system and Epigenetic Landscape of Urological Tumors

Androgen Receptor Signaling and Metabolic and Cellular Plasticity During Progression to Castration Resistant Prostate Cancer

MicroRNAs in treatment-induced neuroendocrine differentiation in prostate cancer

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