New insight into mechanisms of castration resistance

Payton, Sarah

doi:10.1038/nrurol.2010.171

Cited by 3 publications

(3 citation statements)

References 2 publications

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“…AR is a clinically confirmed key player in the progression of prostate cancer as blockade of androgens by surgical or chemical means has formed a vital part of clinical management for many decades [49]. As prostate cancers inevitably become resistant to androgen deprivation therapy, the molecular underpinnings of AR, its effects, regulation and interactions within pathways, remains a central theme in contemporary prostate cancer research with respect to therapy and biology [50, 51]. Using our filtering approach, we were able to observe the decreased methylation of the AR promoter in tumour tissue compared with benign prostate gland samples.…”

Section: Resultsmentioning

confidence: 99%

Reducing the risk of false discovery enabling identification of biologically significant genome-wide methylation status using the HumanMethylation450 array

et al. 2014

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BackgroundThe Illumina HumanMethylation450 BeadChip (HM450K) measures the DNA methylation of 485,512 CpGs in the human genome. The technology relies on hybridization of genomic fragments to probes on the chip. However, certain genomic factors may compromise the ability to measure methylation using the array such as single nucleotide polymorphisms (SNPs), small insertions and deletions (INDELs), repetitive DNA, and regions with reduced genomic complexity. Currently, there is no clear method or pipeline for determining which of the probes on the HM450K bead array should be retained for subsequent analysis in light of these issues.ResultsWe comprehensively assessed the effects of SNPs, INDELs, repeats and bisulfite induced reduced genomic complexity by comparing HM450K bead array results with whole genome bisulfite sequencing. We determined which CpG probes provided accurate or noisy signals. From this, we derived a set of high-quality probes that provide unadulterated measurements of DNA methylation.ConclusionsOur method significantly reduces the risk of false discoveries when using the HM450K bead array, while maximising the power of the array to detect methylation status genome-wide. Additionally, we demonstrate the utility of our method through extraction of biologically relevant epigenetic changes in prostate cancer.Electronic supplementary materialThe online version of this article (doi:10.1186/1471-2164-15-51) contains supplementary material, which is available to authorized users.

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Section: Resultsmentioning

confidence: 99%

Reducing the risk of false discovery enabling identification of biologically significant genome-wide methylation status using the HumanMethylation450 array

et al. 2014

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“…The mainstay treatment for advanced PCa involves targeting of the androgen receptor (AR) signaling pathway 15 . Although most patients initially respond to treatment, many progress to develop Castration-Resistant Prostate Cancer (CRPC) 14 , 16 . The main oncogenic driver of CRPC is sustained signaling by the AR 17 – 21 .…”

Section: Introductionmentioning

confidence: 99%

Histone methyltransferase DOT1L coordinates AR and MYC stability in prostate cancer

et al. 2020

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The histone methyltransferase DOT1L methylates lysine 79 (K79) on histone H3 and is involved in Mixed Lineage Leukemia (MLL) fusion leukemogenesis; however, its role in prostate cancer (PCa) is undefined. Here we show that DOT1L is overexpressed in PCa and is associated with poor outcome. Genetic and chemical inhibition of DOT1L selectively impaired the viability of androgen receptor (AR)-positive PCa cells and organoids, including castration-resistant and enzalutamide-resistant cells. The sensitivity of AR-positive cells is due to a distal K79 methylation-marked enhancer in the MYC gene bound by AR and DOT1L not present in AR-negative cells. DOT1L inhibition leads to reduced MYC expression and upregulation of MYC-regulated E3 ubiquitin ligases HECTD4 and MYCBP2, which promote AR and MYC degradation. This leads to further repression of MYC in a negative feed forward manner. Thus DOT1L selectively regulates the tumorigenicity of AR-positive prostate cancer cells and is a promising therapeutic target for PCa.

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“…Tagawa et al [49] , with a cohort of 54 CRPC patients, reported the presence of AR-V7 splice variant in 36 patients (67%), ARv567e in 42 patients (78%), and the presence of both variants in 29 (54%) patients, but in 5 patients, both variants were absent. Previously, it was supposed that AR splice variants activate AR signaling independent of full-length AR, but it was found that ARv567e binds with full length AR to initiate ligand independent AR signaling which results in the cellular proliferation in the absence of androgen [50] . Apart from these two major AR-Vs other splice variants have been detected in CRPC such as AR-V1, AR-V2, AR-V3, AR-V4, AR-V5, AR-V6, AR-V8, and up to AR-V14 [51] .…”

Section: Ar-dependent Resistance Mechanismsmentioning

confidence: 99%

Resistance to second generation antiandrogens in prostate cancer: pathways and mechanisms

Verma¹,

Prajapati²,

Kushwaha³

et al. 2020

CDR

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Androgen deprivation therapy targeting the androgens/androgen receptor (AR) signaling continues to be the mainstay treatment of advanced-stage prostate cancer. The use of second-generation antiandrogens, such as abiraterone acetate and enzalutamide, has improved the survival of prostate cancer patients; however, a majority of these patients progress to castration-resistant prostate cancer (CRPC). The mechanisms of resistance to antiandrogen treatments are complex, including specific mutations, alternative splicing, and amplification of oncogenic proteins resulting in dysregulation of various signaling pathways. In this review, we focus on the major mechanisms of acquired resistance to second generation antiandrogens, including AR-dependent and ARindependent resistance mechanisms as well as other resistance mechanisms leading to CRPC emergence. Evolving knowledge of resistance mechanisms to AR targeted treatments will lead to additional research on designing more effective therapies for advanced-stage prostate cancer.

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New insight into mechanisms of castration resistance

Cited by 3 publications

References 2 publications

Reducing the risk of false discovery enabling identification of biologically significant genome-wide methylation status using the HumanMethylation450 array

Reducing the risk of false discovery enabling identification of biologically significant genome-wide methylation status using the HumanMethylation450 array

Histone methyltransferase DOT1L coordinates AR and MYC stability in prostate cancer

Resistance to second generation antiandrogens in prostate cancer: pathways and mechanisms

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