Integration of Regulatory Networks by NKX3-1 Promotes Androgen-Dependent Prostate Cancer Survival

Tan, Peck Yean; Chang, Chien-Chi; Chng, Kern Rei; Wansa, K. D. Senali Abayratna; Sung, Wing-Kin; Cheung, Edwin

doi:10.1128/mcb.05958-11

Cited by 158 publications

(159 citation statements)

References 77 publications

(96 reference statements)

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“…17). For example, in the genomic locus of NK3 homeobox 1 (NKX3.1), an AR collaborative factor 33 , we detected decreased 5-hmC levels in BicR cells and increased 5-hmC levels following anti-miR-29b transfection around FOXA1-bound enhancer region (Fig. 6g).…”

Section: Resultsmentioning

confidence: 94%

TET2 repression by androgen hormone regulates global hydroxymethylation status and prostate cancer progression

et al. 2015

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Modulation of epigenetic patterns has promising efficacy for treating cancer. 5-Hydroxymethylated cytosine (5-hmC) is an epigenetic mark potentially important in cancer. Here we report that 5-hmC is an epigenetic hallmark of prostate cancer (PCa) progression. A member of the ten-eleven translocation (TET) proteins, which catalyse the oxidation of methylated cytosine (5-mC) to 5-hmC, TET2, is repressed by androgens in PCa. Androgen receptor (AR)-mediated induction of the miR-29 family, which targets TET2, are markedly enhanced in hormone refractory PCa (HRPC) and its high expression predicts poor outcome of PCa patients. Furthermore, decreased expression of miR-29b results in reduced tumour growth and increased TET2 expression in an animal model of HRPC. Interestingly, global 5-hmC modification regulated by miR-29b represses FOXA1 activity. A reduction in 5-hmC activates PCa-related key pathways such as mTOR and AR. Thus, DNA modification directly links the TET2-dependent epigenetic pathway regulated by AR to 5-hmC-mediated tumour progression.

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Section: Resultsmentioning

confidence: 94%

TET2 repression by androgen hormone regulates global hydroxymethylation status and prostate cancer progression

et al. 2015

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“…Recent reports have demonstrated enrichment of possible ELK1 binding sites in relation to chromatin sites of AR binding (52)(53)(54). The observation that ELK1, fully or in part, supported a substantial proportion (ϳ27%) of all gene activation (direct or indirect) by androgen in PC cells suggests that only a few ARtethering proteins may be adequate to direct AR signaling toward supporting growth.…”

Section: Discussionmentioning

confidence: 99%

The ETS Domain Transcription Factor ELK1 Directs a Critical Component of Growth Signaling by the Androgen Receptor in Prostate Cancer Cells

Patki

Chari

Sivakumaran

et al. 2013

Journal of Biological Chemistry

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Background: Mechanisms that redirect androgen receptor signaling to primarily support prostate tumor growth are poorly understood. Results: Prostate cancer cells were addicted to ELK1, which tethered AR to activate growth genes in hormone-dependent and castration-recurrent PC without ELK1 phosphorylation. Conclusion: ELK1 directs a critical arm of transcriptional growth signaling by AR that is preserved in CRPC. Significance: The ELK1-AR interaction offers a functionally tumor-selective drug target.

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“…The numbers shown in the parentheses correspond to the average number of SNPs required to identify 50 and 80% of the causal SNPs, respectively. histone methylation (He et al 2010;Wang et al 2011;Bert et al 2013;Hazelett et al 2014), and transcription factor bindings (Tan et al 2012; The ENCODE Project Consortium 2012; Sharma et al 2013;Hazelett et al 2014;Takayama et al 2014). All annotations were aligned to human genome version 19 coordinates.…”

Section: Annotations Used For Eqtl Datamentioning

confidence: 99%

Incorporating Functional Annotations for Fine-Mapping Causal Variants in a Bayesian Framework Using Summary Statistics

et al. 2016

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Functional annotations have been shown to improve both the discovery power and fine-mapping accuracy in genomewide association studies. However, the optimal strategy to incorporate the large number of existing annotations is still not clear. In this study, we propose a Bayesian framework to incorporate functional annotations in a systematic manner. We compute the maximum a posteriori solution and use cross validation to find the optimal penalty parameters. By extending our previous fine-mapping method CAVIARBF into this framework, we require only summary statistics as input. We also derived an exact calculation of Bayes factors using summary statistics for quantitative traits, which is necessary when a large proportion of trait variance is explained by the variants of interest, such as in fine mapping expression quantitative trait loci (eQTL). We compared the proposed method with PAINTOR using different strategies to combine annotations. Simulation results show that the proposed method achieves the best accuracy in identifying causal variants among the different strategies and methods compared. We also find that for annotations with moderate effects from a large annotation pool, screening annotations individually and then combining the top annotations can produce overly optimistic results. We applied these methods on two real data sets: a meta-analysis result of lipid traits and a cis-eQTL study of normal prostate tissues. For the eQTL data, incorporating annotations significantly increased the number of potential causal variants with high probabilities.KEYWORDS Bayesian fine mapping; annotations; summary statistics; causal variants A large amount of annotation information of genomic elements has been generated, such as the Encyclopedia of DNA Elements (The ENCODE Project Consortium 2012). Regulatory elements, such as those marked by DNase I hypersensitive sites (DHSs), have been shown to be enriched with associations and explain a large proportion of heritability (Maurano et al. 2012;Gusev et al. 2014). Incorporation of these annotations into statistical association analyses can improve both the power in genome-wide association study (GWAS) discovery (Pickrell 2014) and the accuracy in fine mapping underlying causal variants (Quintana and Conti 2013;Kichaev et al. 2014;Wen et al. 2015). However, the number of annotations is often very large and many of them may not be informative for the underlying causal genetic variants. Currently, there is no systematic and effective way to incorporate a large number of annotations in association analyses, which is crucial to the full use of the available information. In practice, usually only a small number of annotations are considered (Quintana and Conti 2013;Wen et al. 2015). A recent proposed algorithm, PAINTOR, suggests a one-by-one test of each annotation selecting the top 4-5 for inclusion. This has potential to waste the information from the remaining annotations, which may together provide significant predictive power of the causal status. Another approach...

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Integration of Regulatory Networks by NKX3-1 Promotes Androgen-Dependent Prostate Cancer Survival

Cited by 158 publications

References 77 publications

TET2 repression by androgen hormone regulates global hydroxymethylation status and prostate cancer progression

TET2 repression by androgen hormone regulates global hydroxymethylation status and prostate cancer progression

The ETS Domain Transcription Factor ELK1 Directs a Critical Component of Growth Signaling by the Androgen Receptor in Prostate Cancer Cells

Incorporating Functional Annotations for Fine-Mapping Causal Variants in a Bayesian Framework Using Summary Statistics

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