Integrative analysis reveals disease-associated genes and biomarkers for prostate cancer progression

Li, Yin; Vongsangnak, Wanwipa; Chen, Luonan; Shen, Bairong

doi:10.1186/1755-8794-7-s1-s3

Cited by 23 publications

(18 citation statements)

References 84 publications

(85 reference statements)

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“…We observed no significant difference in gene expression between mock and NCsiRNA treated cells. EGFR siRNA treatment inhibited expression of EGFR (4.4 fold), IGF1 (17.8 fold) and ESR1 (4.52 fold vs. NCsiRNA expression) genes, that have been described earlier with respect of EGFR signaling [18][19][20][21]. Similarly, the RFE-siEGFR treatment inhibited EGFR (2.4 fold), IGF1 (13.7 fold) and ESR1 (4.4 fold, Fig.…”

Section: Rfe Gene Knockdownmentioning

confidence: 51%

Precision knockdown of EGFR gene expression using radio frequency electromagnetic energy

et al. 2017

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Electromagnetic fields (EMF) in the radio frequency energy (RFE) range can affect cells at the molecular level. Here we report a technology that can record the specific RFE signal of a given molecule, in this case the siRNA of epidermal growth factor receptor (EGFR). We demonstrate that cells exposed to this EGFR siRNA RFE signal have a 30-70% reduction of EGFR mRNA expression and ~60% reduction in EGFR protein expression vs. control treated cells. Specificity for EGFR siRNA effect was confirmed via RNA microarray and antibody dot blot array. The EGFR siRNA RFE decreased cell viability, as measured by Calcein-AM measures, LDH release and Caspase 3 cleavage, and increased orthotopic xenograft survival. The outcomes of this study demonstrate that an RFE signal can induce a specific siRNA-like effect on cells. This technology opens vast possibilities of targeting a broader range of molecules with applications in medicine, agriculture and other areas.

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Section: Rfe Gene Knockdownmentioning

confidence: 51%

Precision knockdown of EGFR gene expression using radio frequency electromagnetic energy

et al. 2017

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“…Interestingly, also enriched under androgen deprivation, as well as with androgen treatment, were several other members of the ETS family of transcription factors (Fig 8A and S12A Fig). In the presence of androgens, the most enriched motif corresponded not to ELK1 but to SP1, an AR-interacting protein upregulated in prostate cancer (S12A Fig) [42]. SP1 is reported to promote AR target gene expression in response to androgens and to occupy sites near gene promoters [43, 44].…”

Section: Resultsmentioning

confidence: 99%

MED19 alters AR occupancy and gene expression in prostate cancer cells, driving MAOA expression and growth under low androgen

Weber

Ruoff

Garabedian

2019

Preprint

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Androgen deprivation therapy (ADT) is a mainstay of prostate cancer treatment, given the dependence of prostate cells on androgen and the androgen receptor (AR). However, tumors become ADT-resistant, and there is a need to understand the mechanism. One possible mechanism is the upregulation of AR co-regulators, although only a handful have been definitively linked to disease. We previously identified the Mediator subunit MED19 as an AR co-regulator, and reported that MED19 depletion inhibits AR transcriptional activity and growth of androgen-insensitive LNCaP-abl cells. Therefore, we proposed that MED19 upregulation would promote AR activity and drive androgen-independent growth. Here, we show that stable overexpression of MED19 in androgen-dependent LNCaP cells promotes growth under conditions of androgen deprivation. To delineate the mechanism, we determined the MED19 and AR transcriptomes and cistromes in control and MED19 LNCaP cells. We also examined H3K27 acetylation genome-wide. MED19 overexpression selectively alters AR occupancy, H3K27 acetylation, and gene expression. Under conditions of androgen deprivation, genes regulated by MED19 and genomic sites occupied by MED19 and AR are enriched for ELK1, a transcription factor that binds the AR N-terminus to promote select AR-target gene expression. Strikingly, MED19 upregulates expression of monoamine oxidase A (MAOA), a factor that promotes prostate cancer growth. MAOA depletion reduces androgen-independent growth. MED19 and AR occupy the MAOA promoter, with MED19 overexpression enhancing AR occupancy and H3K27 acetylation. Furthermore, MED19 overexpression increases ELK1 occupancy at the MAOA promoter, and ELK1 depletion reduces MAOA expression and androgen-independent growth. This suggests that MED19 cooperates with ELK1 to regulate AR occupancy and H3K27 acetylation at MAOA, upregulating its expression and driving androgen independence in prostate cancer cells. This study provides important insight into the mechanisms of prostate cancer cell growth under low androgen, and underscores the importance of the MED19-MAOA axis in this process.Author summaryProstate cancer is one of the most common cancers worldwide, and androgen hormones are essential for prostate cancer growth. Androgens exert their effects through a protein called the androgen receptor (AR), which turns on and off genes that regulate prostate cancer growth. Powerful drugs that block AR action by lowering androgen levels – so-called androgen deprivation therapy - are used to treat prostate cancer patients, and these yield initial success in reducing tumor growth. However, over time, tumors circumvent androgen deprivation therapy and patients relapse; in many cases, this occurs because AR becomes re-activated. The factors responsible for re-activating AR and promoting growth under androgen deprivation are not well understood. Here, we demonstrate that a subunit of the Mediator transcriptional regulatory complex, called MED19, promotes growth of prostate cancer cells under low androgen conditions, mimicking the ability of tumors to grow under androgen deprivation in prostate cancer patients. MED19 promotes androgen-independent growth by working with a transcription factor that interacts with AR, called ELK1, to induce the expression of genes regulated by AR that promote prostate cancer growth. This study provides important insight into how prostate cancer cells can maintain growth under androgen deprivation through MED19.

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“…demonstrated that -216 SNP in the EGFR promoter was associated with altered promoter activity by Sp1 binding and gene expression both in vitro and in vivo (72). SP1 has been shown to directly or indirectly regulate some PCa related genes, of which EGFR is one (73). …”

Section: Discussionmentioning

confidence: 99%

Coexpression and expression quantitative trait loci analyses of the angiogenesis gene-gene interaction network in prostate cancer

et al. 2016

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Background Prostate cancer (PCa) shows a substantial clinical heterogeneity. The existing risk classification for PCa prognosis based on clinical factors is not sufficient. Although some biomarkers for PCa aggressiveness have been identified, their underlying functional mechanisms are still unclear. We previously reported a gene-gene interaction network associated with PCa aggressiveness based on single nucleotide polymorphism (SNP)-SNP interactions in the angiogenesis pathway. The goal of this study is to investigate potential functional evidence of the involvement of the genes in this gene-gene interaction network. Methods A total of 11 angiogenesis genes were evaluated. The crosstalks among genes were examined through coexpression and expression quantitative trait loci (eQTL) analyses. The study population is 352 Caucasian PCa patients in the Cancer Genome Atlas (TCGA) study. The pairwise coexpressions among the genes of interest were evaluated using the Spearman coefficient. The eQTL analyses were tested using the Kruskal-Wallis test. Results Among all within gene and 55 possible pairwise gene evaluations, 12 gene pairs and one gene (MMP16) showed strong coexpression or significant eQTL evidence. There are nine gene pairs with a strong correlation (Spearman correlation ≥0.6, P<1×10−13). The top coexpressed gene pairs are EGFR-SP1 (r=0.73), ITGB3-HSPG2 (r=0.71), ITGB3-CSF1 (r=0.70), MMP16-FBLN5 (r=0.68), ITGB3-MMP16 (r=0.65), ITGB3-ROBO1 (r=0.62), CSF1-HSPG2 (r=0.61), CSF1-FBLN5 (r=0.6), and CSF1-ROBO1 (r=0.60). One cis-eQTL in MMP16 and five trans-eQTLs (MMP16-ESR1, ESR1-ROBO1, CSF1-ROBO1, HSPG2-ROBO1, and FBLN5-CSF1) are significant with a false discovery rate q value less than 0.2. Conclusions These findings provide potential biological evidence for the gene-gene interactions in this angiogenesis network. These identified interactions between the angiogenesis genes not only provide information for PCa etiology mechanism but also may serve as integrated biomarkers for building a risk prediction model for PCa aggressiveness.

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Integrative analysis reveals disease-associated genes and biomarkers for prostate cancer progression

Cited by 23 publications

References 84 publications

Precision knockdown of EGFR gene expression using radio frequency electromagnetic energy

Precision knockdown of EGFR gene expression using radio frequency electromagnetic energy

MED19 alters AR occupancy and gene expression in prostate cancer cells, driving MAOA expression and growth under low androgen

Coexpression and expression quantitative trait loci analyses of the angiogenesis gene-gene interaction network in prostate cancer

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