Alterations of androgen receptor-regulated enhancer RNAs (eRNAs) contribute to enzalutamide resistance in castration-resistant prostate cancer

Zhao, Jingwen; Zhao, Yu; Wang, Liguo; Zhang, Jun; Karnes, Jeffrey; Kohli, Manish; Wang, Guixia; Huang, Haojie

doi:10.18632/oncotarget.9535

Cited by 35 publications

(35 citation statements)

References 59 publications

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“…LUZP2 is a leucine zipper protein coding gene that has been reported to be deleted in some patients with Wilms tumor-Aniridia-Genitourinary anomalies-mental Retardation (WAGR) syndrome [ 17 ]. It has also been reported that LUZP2 was associated with prostate cancer and hypereosinophilic syndrome [ 18 , 19 ]. The function of LUZP2 is still unclear and inhibition of its expression did not show any obvious abnormal phenotypes in mice [ 20 ].…”

Section: Discussionmentioning

confidence: 99%

Genome-wide association study identifies two loci influencing plasma neurofilament light levels

Yuan

et al. 2018

BMC Med Genomics

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BackgroundPlasma neurofilament light (NFL) is a promising biomarker for Alzheimer disease (AD), which increases in the early stage of AD and is associated with the progression of AD. We performed a genome-wide association study (GWAS) of plasma NFL in Alzheimer’s Disease Neuroimaging Initiative 1 (ADNI-1) cohort to identify novel variants associated with AD.MethodsThis study included 179 cognitively healthy controls (HC), 176 patients with mild cognitive impairment (MCI), and 172 patients with AD. All subjects were restricted to non-Hispanic Caucasian derived from the ADNI cohort and met all quality control (QC) criteria. Association of plasma NFL with the genetic variants was assessed using PLINK with an additive genetic model, i.e.dose-dependent effect of the minor alleles. The influence of a genetic variant associated with plasma NFL (rs7943454) on brain structure was further assessed using PLINK with a linear regression model.ResultsThe minor allele (T) of rs7943454 in leucine zipper protein 2 gene (LUZP2) was associated with higher plasma NFL at suggestive levels (P = 1.39 × 10− 6) in a dose-dependent fashion. In contrast, the minor allele (G) of rs640476 near GABRB2 was associated with lower plasma NFL at suggestive levels (P = 6.71 × 10− 6) in a dose-dependent effect in all diagnostic groups except the MCI group. Furthermore, the minor allele (T) of rs7943454 within LUZP2 increased the onset risk of AD (odds ratio = 1.547, confidence interval 95% = 1.018–2.351) and was associated with atrophy of right middle temporal gyrus in the whole cohort in the longitudinal study (P = 0.0234).ConclusionGWAS found the associations of two single nucleotide polymorphisms (rs7943454 and rs640476) with plasma NFL at suggestive levels. Rs7943454 in LUZP2 was associated with the onset risk of AD and atrophy of right middle temporal gyrusin the whole cohort. Using an endophenotype-based approach, we identified rs7943454 as a new AD risk locus.Electronic supplementary materialThe online version of this article (10.1186/s12920-018-0364-8) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Genome-wide association study identifies two loci influencing plasma neurofilament light levels

Yuan

et al. 2018

BMC Med Genomics

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“…Interestingly, a group of AR-regulated eRNAs was recently shown to be up-regulated also in CRPC patient specimens 41 . Moreover, long-term enzalutamide, a second generation antiandrogen, treatment was reported to induce alterations in AR-regulated eRNAs, which was suggested to contribute to enzalutamide resistance in CRPC 42 .…”

Section: Discussionmentioning

confidence: 99%

Global analysis of transcription in castration-resistant prostate cancer cells uncovers active enhancers and direct androgen receptor targets

Toropainen

Niskanen

Malinen

et al. 2016

Sci Rep

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Androgen receptor (AR) is a male sex steroid-activated transcription factor (TF) that plays a critical role in prostate cancers, including castration-resistant prostate cancers (CRPC) that typically express amplified levels of the AR. CRPC-derived VCaP cells display an excessive number of chromatin AR-binding sites (ARBs) most of which localize to distal inter- or intragenic regions. Here, we analyzed direct transcription programs of the AR in VCaP cells using global nuclear run-on sequencing (GRO-seq) and integrated the GRO-seq data with the ARB and VCaP cell-specific TF-binding data. Androgen immediately activated transcription of hundreds of protein-coding genes, including IGF-1 receptor and EGF receptor. Androgen also simultaneously repressed transcription of a large number of genes, including MYC. As functional enhancers have been postulated to produce enhancer-templated non-coding RNAs (eRNAs), we also analyzed the eRNAs, which revealed that only a fraction of the ARBs reside at functional enhancers. Activation of these enhancers was most pronounced at the sites that also bound PIAS1, ERG and HDAC3, whereas binding of HDAC3 and PIAS1 decreased at androgen-repressed enhancers. In summary, our genome-wide data of androgen-regulated enhancers and primary target genes provide new insights how the AR can directly regulate cellular growth and control signaling pathways in CPRC cells.

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“…As MBC is generally ERα driven, we suggest a similar action of ERα in MBC to FBC, which may also indicate the potential 24:3 for outcome determination of male breast cancers on the basis of differential ERα binding. In addition, several groups have profiled AR/DNA binding in prostate cancer and have shown associations of distinct AR signatures with outcome (Stelloo et al 2015, Zhao et al 2016a. These findings indicate that these techniques can be applied to breast tumor samples as well, to better characterize the functional binding patterns of both ERα and AR in male breast cancer in relation to patient prognostication.…”

Section: Molecular Featuresmentioning

confidence: 95%

A review of estrogen receptor/androgen receptor genomics in male breast cancer

Severson¹,

Zwart²

2017

Endocrine-Related Cancer

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Male breast cancer is a rare disease, of which little is known. In contrast to female breast cancer, the very vast majority of all cases are positive for estrogen receptor alpha (ERα), implicating the function of this steroid hormone receptor in tumor development and progression. Consequently, adjuvant treatment of male breast cancer revolves around inhibition of ERα. In addition, the androgen receptor (AR) gradually receives more attention as a relevant novel target in breast cancer treatment. Importantly, the rationale of treatment decision making is strongly based on parallels with female breast cancer. Yet, prognostic indicators are not necessarily the same in breast cancer between both genders, complicating translatability of knowledge developed in female breast cancer toward male patients. Even though ERα and AR are expressed both in female and male disease, are the genomic functions of both steroid hormone receptors conserved between genders? Recent studies have reported on mutational and epigenetic similarities and differences between male and female breast cancer, further suggesting that some features are strongly conserved between the two diseases, whereas others are not. This review critically discusses the recent developments in the study of male breast cancer in relation to ERα and AR action and highlights the potential future studies to further elucidate the genomic regulation of this rare disease.

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Alterations of androgen receptor-regulated enhancer RNAs (eRNAs) contribute to enzalutamide resistance in castration-resistant prostate cancer

Cited by 35 publications

References 59 publications

Genome-wide association study identifies two loci influencing plasma neurofilament light levels

Genome-wide association study identifies two loci influencing plasma neurofilament light levels

Global analysis of transcription in castration-resistant prostate cancer cells uncovers active enhancers and direct androgen receptor targets

A review of estrogen receptor/androgen receptor genomics in male breast cancer

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