Transcriptome analysis reveals a dynamic and differential transcriptional response to sulforaphane in normal and prostate cancer cells and suggests a role for Sp1 in chemoprevention

Beaver, Laura M.; Buchanan, Alex; Sokolowski, Elizabeth; Riscoe, Allison N.; Wong, Carmen P.; Chang, Jeff H.; Löhr, Christiane V.; Williams, David E.; Dashwood, Roderick H.; Ho, Emily

doi:10.1002/mnfr.201400269

Cited by 28 publications

(33 citation statements)

References 43 publications

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“…The exact mechanism is not clear but early research has revealed other transcription factors are also involved in VEGF expression, such as Sp1/ Sp3, AP2, Egr-1 and STAT-2 (44). For example, SFN was found to be able to inhibit STAT and SP1 pathways (45,46). Our finding may suggest that SFN has a potential role in attenuating anticancer resistance.…”

Section: Discussionmentioning

confidence: 58%

Differential effects of sulforaphane in regulation of angiogenesis in a co-culture model of endothelial cells and pericytes

et al. 2017

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Abstract. Aberrant neovascularization supports nutrients and the oxygen microenvironment in tumour growth, invasion and metastasis. Recapitulation of functional microvascular structures in vitro could provide a platform for the study of vascular conditions. Sulforaphane (SFN), an isothiocyanate, has been reported to possess chemopreventive properties. In the present study, the effects of SFN on cell proliferation and tubular formation have been investigated using endothelial cells (ECs) and pericytes in coculture. SFN showed a dosedependent inhibition on the growth of ECs and pericytes with IC 50 values 46.7 and 32.4 µM, respectively. SFN (5-20 µM) inhibited tube formation in a 3D coculture although a lower dose (1.25 µM) promoted 30% more endothelial tube formation than control. Moreover, SFN affected intercellular communication between ECs and pericytes via inhibition of angiogenic factor such as vascular endothelial growth factor (VEGF) expression in pericytes. However, the expression of its receptor (VEGFR-2) was found significantly increased in ECs. These effects were associated with downregulation of prolyl hydroxylase domain-containing protein 1 and 2 (PHD1/2) and activation of hypoxia-inducible factor-1 (HIF) pathway by SFN. Furthermore, thioredoxin reductase-1 was also upregulated by SFN treatment, suggesting that antioxidant and redox regulation are involved in angiogenesis. Taken together, the results of the present study suggest that SFN differentially regulates endothelial cells and pericytes disrupting their interplay through the VEGF-VEGFR signalling pathway. Anti-angiogenesis property of SFN indicates that it has potential role as an anticancer agent. IntroductionAngiogenesis, the growth of new capillary blood vessels, is a normal and vital process in growth, development and wound healing. However, it is also a fundamental step in the growth of tumours. Nutrients and oxygen, supplied by the blood vessels into the tumours, are essential for the growth and progression of malignant tumours beyond the size of 1-2 mm 3 (1). Newly formed blood vessels can facilitate cells escaping through leakage from primary tumour sites to metastasize, the major cause of mortality for cancer patients. Anti-angiogenesis has been recognized as valuable therapy in treatment of various metastatic cancers since the theory was first proposed by Folkman (2,3). Tumour angiogenesis is believed to be regulated by the interactions between pro-angiogenic and anti-angiogenic factors in the tumour microenvironment (4). Angiogenic response is a dynamic process requiring a series of fine-tuned angiogenic signalling and molecular events. Hypoxia is the common inducer of angiogenesis in the core of large tumours stimulating the release of pro-angiogenic factors to promote endothelial cell proliferation, migration, differentiation and self-assembly into vascular-like structures. Subsequently, perivascular cells are recruited to form mature and stable vessels (5).The interaction between endothelial cells (ECs) and pericytes (PVCs) has g...

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Section: Discussionmentioning

confidence: 58%

Differential effects of sulforaphane in regulation of angiogenesis in a co-culture model of endothelial cells and pericytes

et al. 2017

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“…Normal prostate epithelium cells (PREC) were obtained from Lonza (Basel, Switzerland) and cultured as recommended (Lonza) [18, 21]. Androgen-dependent (LNCaP) and androgen-independent (PC-3) prostate cancer cells were obtained from American Type Tissue Collection (Manassas, VA) and cultured as previously described [18].…”

Section: Methodsmentioning

confidence: 99%

“…Cells were treated in triplicate, and total RNA was isolated and subsequently sequenced on an Illumina HiSeq 2000 machine at the Center for Genome Research and Biocomputing core facility at Oregon State University as previously described [21]. Sequencing data were processed in two separate pipelines.…”

Section: Methodsmentioning

confidence: 99%

“…Log2 fold changes that approached infinity were reassigned as 20. The raw RNA-seq reads and differential expression data have been previously deposited in NCBI Gene Expression Omnibus and are accessible through GEO Series accession number GSE48812 (http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE48812) [21]. …”

Section: Methodsmentioning

confidence: 99%

“…Data represent the copy number of the gene of interest normalized to the copy number of the indicated housekeeping gene. GAPDH was used as a housekeeping gene in SFN experiments as previously described [21]. For knockdown experiments β-actin was used as housekeeping due to consistent expression in all knockdown conditions.…”

Section: Methodsmentioning

confidence: 99%

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Long noncoding RNAs and sulforaphane: a target for chemoprevention and suppression of prostate cancer

Beaver

Kuintzle

Buchanan

et al. 2017

The Journal of Nutritional Biochemistry

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Long non-coding RNAs (lncRNAs) have emerged as important in cancer development and progression. The impact of diet on lncRNA expression is largely unknown. Sulforaphane (SFN), obtained from vegetables like broccoli, can prevent and suppress cancer formation. Here we tested the hypothesis that SFN attenuates the expression of cancer-associated lncRNAs. We analyzed whole genome RNA-sequencing data of normal human prostate epithelial cells and prostate cancer cells treated with 15 μM SFN or DMSO. SFN significantly altered expression of ~100 lncRNAs in each cell type, and normalized the expression of some lncRNAs that were differentially expressed in cancer cells. SFN-mediated alterations in lncRNA expression correlated with genes that regulate cell cycle, signal transduction, and metabolism. LINC01116 was functionally investigated because it was overexpressed in several cancers, and was transcriptionally repressed after SFN treatment. Knockdown of LINC01116 with siRNA decreased proliferation of prostate cancer cells, and significantly upregulated several genes including GAPDH (regulates glycolysis), MAP1LC3B2 (autophagy) and H2AFY (chromatin structure). A 4-fold decrease in the ability of the cancer cells to form colonies was found when the LINC01116 gene was disrupted through a CRISPR/CAS9 method, further supporting an oncogenic function for LINC01116 in PC-3 cells.. We identified a novel isoform of LINC01116 and bioinformatically investigated the possibility that LINC01116 could interact with target genes via ssRNA:dsDNA triplexes. Our data reveal that chemicals from the diet can influence the expression of functionally important lncRNAs, and suggest a novel mechanism by which SFN may prevent and suppress prostate cancer.

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Oncogenic targets Mmp7, S100a9, Nppb and Aldh1a3 from transcriptome profiling of FAP and Pirc adenomas are downregulated in response to tumor suppression by Clotam

Ertem

Zhang

Chang

et al. 2016

Intl Journal of Cancer

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Intervention strategies in familial adenomatous polyposis (FAP) patients and other high-risk colorectal cancer (CRC) populations have highlighted a critical need for endoscopy combined with safe and effective preventive agents. We performed transcriptome profiling of colorectal adenomas from FAP patients and the polyposis in rat colon (Pirc) preclinical model, and prioritized molecular targets for prevention studies in vivo. At clinically relevant doses in the Pirc model, the drug Clotam (tolfenamic acid, TA) was highly effective at suppressing tumorigenesis both in the colon and in the small intestine, when administered alone or in combination with Sulindac. Cell proliferation in the colonic crypts was reduced significantly by TA, coincident with increased cleaved caspase-3 and decreased Survivin, β-catenin, cyclin D1 and matrix metalloproteinase 7. From the list of differentially expressed genes prioritized by transcriptome profiling, Mmp7, S100a9, Nppb and Aldh1a3 were defined as key oncogene candidates downregulated in colon tumors after TA treatment. Monthly colonoscopies revealed the rapid onset of tumor suppression by TA in the Pirc model, and the temporal changes in Mmp7, S100a9, Nppb and Aldh1a3, highlighting their value as potential early biomarkers for prevention in the clinical setting. We conclude that TA, an "old drug" repurposed from migraine, offers an exciting new therapeutic avenue in FAP and other high-risk CRC patient populations.

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Transcriptome analysis reveals a dynamic and differential transcriptional response to sulforaphane in normal and prostate cancer cells and suggests a role for Sp1 in chemoprevention

Cited by 28 publications

References 43 publications

Differential effects of sulforaphane in regulation of angiogenesis in a co-culture model of endothelial cells and pericytes

Differential effects of sulforaphane in regulation of angiogenesis in a co-culture model of endothelial cells and pericytes

Long noncoding RNAs and sulforaphane: a target for chemoprevention and suppression of prostate cancer

Oncogenic targets Mmp7, S100a9, Nppb and Aldh1a3 from transcriptome profiling of FAP and Pirc adenomas are downregulated in response to tumor suppression by Clotam

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