title: Phenethyl isothiocyanate (PEITC) suppresses prostate cancer cell invasion epigenetically through regulating microRNA-194.
abstract: Tumor metastasis greatly contributes to the mortality of prostate cancer. The glucosinolate-derived phenethyl isothiocyanate (PEITC) has been widely documented to reduce the risk of prostate cancer by modulating multiple biologically relevant processes. Emerging evidence suggests that PEITC may exert its anti-cancer effects through epigenetic mechanisms including microRNAs. Altered levels of miRNA have been linked to tumor malignancy due to their capacity to regulate functional gene expression in carcinogenesis. Here, we assessed the effects of PEITC on miRNA expression which is related to PCa cell invasiveness.
  
  
  
  Utilizing oligonucleotide microarray first identified the most affected miRNAs in LNCaP cells after PEITC treatment. Several top altered miRNAs were further validated using quantitative PCR. Interestingly, overexpression of miR-194 suppressed PC3 cell invasion in matrigel-coated Transwell chambers. Bone morphogenetic protein 1 (BMP1) was shown to be a direct target of miR-194. Downregulation of BMP1 by miR-194 or PEITC led to decreased expression of key oncogenic matrix metalloproteinases, MMP2 and MMP9. This in turn resulted in the suppression of tumor invasion.
  
  
  
  Our results indicate that miR-194 downregulates the expression of oncogenic MMP2 and MMP9 by targeting BMP1, which suggests a potential new mechanistic target by which PEITC suppresses prostate cancer cell invasiveness.
authors.affiliation: Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, the State University of New Jersey, USA.|Center for Cancer Prevention Research, Ernest Mario School of Pharmacy, Rutgers, , the State University of New Jersey, USA.|Center for Epigenomics of CAM Natural Products, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, USA.
authors.forename: Chengyue
authors.initials: C
authors.lastname: Zhang
authors.affiliation: Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, the State University of New Jersey, USA.|Center for Cancer Prevention Research, Ernest Mario School of Pharmacy, Rutgers, , the State University of New Jersey, USA.
authors.forename: Limin
authors.initials: L
authors.lastname: Shu
authors.affiliation: Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, the State University of New Jersey, USA.|Center for Cancer Prevention Research, Ernest Mario School of Pharmacy, Rutgers, , the State University of New Jersey, USA.
authors.forename: Hyuck
authors.initials: H
authors.lastname: Kim
authors.affiliation: Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, the State University of New Jersey, USA.|Center for Cancer Prevention Research, Ernest Mario School of Pharmacy, Rutgers, , the State University of New Jersey, USA.
authors.forename: Tin Oo
authors.initials: TO
authors.lastname: Khor
authors.affiliation: Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, the State University of New Jersey, USA.|Center for Cancer Prevention Research, Ernest Mario School of Pharmacy, Rutgers, , the State University of New Jersey, USA.|Center for Epigenomics of CAM Natural Products, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, USA.
authors.forename: Renyi
authors.initials: R
authors.lastname: Wu
authors.affiliation: Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, the State University of New Jersey, USA.|Center for Cancer Prevention Research, Ernest Mario School of Pharmacy, Rutgers, , the State University of New Jersey, USA.|Center for Epigenomics of CAM Natural Products, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, USA.
authors.forename: Wenji
authors.initials: W
authors.lastname: Li
authors.affiliation: Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, the State University of New Jersey, USA.|Center for Cancer Prevention Research, Ernest Mario School of Pharmacy, Rutgers, , the State University of New Jersey, USA.|Center for Epigenomics of CAM Natural Products, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, USA.
authors.forename: Ah-Ng Tony
authors.initials: AN
authors.lastname: Kong
mesh_terms: D055395:Bone Morphogenetic Protein 1 / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D044127:Epigenesis, Genetic; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D017879:Isothiocyanates / Q000494:pharmacology*; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D009361:Neoplasm Invasiveness / Q000235:genetics*; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000235:genetics*
chemical_list: D017879:Isothiocyanates; C554846:MIRN194 microRNA, human; D035683:MicroRNAs; C058305:phenethyl isothiocyanate; C525705:BMP1 protein, human; D055395:Bone Morphogenetic Protein 1; C522361:MMP2 protein, human; D020778:Matrix Metalloproteinase 2; C579270:MMP9 protein, human; D020780:Matrix Metalloproteinase 9
keywords: Cell invasion; Mir-194; Phenethyl isothiocyanate; Prostate cancer; microRNA
references.citation: Stem Cells. 2009 Aug;27(8):1712-21
references.pmid: 19544444
references.citation: Cancer Sci. 2011 Jan;102(1):9-17
references.pmid: 20735434
references.citation: Am J Pathol. 2008 Sep;173(3):856-64
references.pmid: 18688024
references.citation: EMBO J. 2004 Oct 13;23(20):4051-60
references.pmid: 15372072
references.citation: Oncogene. 2008 Mar 13;27(12):1788-93
references.pmid: 17891175
references.citation: Ann Surg Oncol. 2012 Jul;19 Suppl 3:S509-17
references.pmid: 21845495
references.citation: Food Chem Toxicol. 1995 Jun;33(6):537-43
references.pmid: 7797181
references.citation: Exp Cell Res. 2014 Jan 15;320(2):188-99
references.pmid: 24135225
references.citation: Cancer Cell. 2010 Oct 19;18(4):367-81
references.pmid: 20951946
references.citation: Nature. 2005 Jun 9;435(7043):828-33
references.pmid: 15944707
references.citation: Mol Biol Cell. 1999 Feb;10(2):407-16
references.pmid: 9950685
references.citation: Cancer Res. 2011 Jan 1;71(1):225-33
references.pmid: 21199804
references.citation: Prostate Cancer Prostatic Dis. 2010 Sep;13(3):208-17
references.pmid: 20585343
references.citation: Science. 2000 Aug 18;289(5482):1197-202
references.pmid: 10947988
references.citation: Mol Cell. 2007 Jul 6;27(1):91-105
references.pmid: 17612493
references.citation: Anticancer Agents Med Chem. 2012 Dec;12(10):1281-305
references.pmid: 22583408
references.citation: Cancer Epidemiol Biomarkers Prev. 2000 Aug;9(8):795-804
references.pmid: 10952096
references.citation: Hepatology. 2010 Dec;52(6):2148-57
references.pmid: 20979124
references.citation: Br J Cancer. 2000 Jan;82(1):249
references.pmid: 10638999
references.citation: Oncogene. 2014 Jan 9;33(2):135-47
references.pmid: 23455326
references.citation: Hepatology. 2012 Jan;55(1):98-107
references.pmid: 21887698
references.citation: Oncogene. 2014 Mar 20;33(12):1506-14
references.pmid: 23584484
references.citation: Mol Nutr Food Res. 2013 Oct;57(10):1825-33
references.pmid: 23661605
references.citation: Proc Natl Acad Sci U S A. 2010 May 4;107(18):8231-6
references.pmid: 20406904
references.citation: RNA. 2004 Oct;10(10):1507-17
references.pmid: 15383676
references.citation: Carcinogenesis. 2010 May;31(5):894-901
references.pmid: 20145010
references.citation: Asian Pac J Cancer Prev. 2013;14(3):1565-70
references.pmid: 23679237
references.citation: Nat Genet. 2005 May;37(5):495-500
references.pmid: 15806104
references.citation: Cancer Res. 2007 Jun 15;67(12 ):5699-707
references.pmid: 17575136
references.citation: Oncogene. 2007 Jun 14;26(28):4148-57
references.pmid: 17260024
references.citation: Int J Oncol. 2014 Oct;45(4):1437-49
references.pmid: 25096247
references.citation: PLoS One. 2013 May 28;8(5):e64535
references.pmid: 23724058
references.citation: Am J Transl Res. 2012;4(1):14-23
references.pmid: 22347519
references.citation: Nat Genet. 2006 Sep;38(9):1060-5
references.pmid: 16878133
references.citation: J Cell Biol. 2006 Oct 9;175(1):111-20
references.pmid: 17015622
references.citation: Cancer Res. 1994 Aug 15;54(16):4327-33
references.pmid: 8044780
references.citation: Prostate. 2011 Apr;71(5):538-49
references.pmid: 20886540
references.citation: Cancer Res. 1998 Sep 15;58(18):4102-6
references.pmid: 9751619
references.citation: Adv Exp Med Biol. 1996;401:13-23
references.pmid: 8886123
references.citation: AAPS J. 2010 Mar;12 (1):87-97
references.pmid: 20013083
references.citation: Cell Death Differ. 2013 Dec;20(12):1603-14
references.pmid: 24212931
references.citation: Mol Cancer. 2011 Aug 18;10 :99
references.pmid: 21851624
references.citation: Mol Cell Biol. 2014 Jul;34(13):2382-95
references.pmid: 24732804
references.citation: Cancer Res. 2010 Oct 15;70(20):8108-16
references.pmid: 20813833
references.citation: Mol Carcinog. 2007 Jan;46(1):24-31
references.pmid: 16921492
references.citation: Nat Cell Biol. 2009 Mar;11(3):228-34
references.pmid: 19255566
references.citation: Biochem Pharmacol. 2010 Dec 15;80(12):1771-92
references.pmid: 20599773
references.citation: Nucleic Acids Res. 2012 May;40(10):4615-25
references.pmid: 22210897
references.citation: Nat Rev Cancer. 2012 Jul;12 (7):445-6
references.pmid: 22912952
references.citation: Pharm Res. 2010 Jun;27(6):1014-26
references.pmid: 20221895
references.citation: Proc Natl Acad Sci U S A. 2008 Oct 7;105(40):15535-40
references.pmid: 18832181
references.citation: Nat Rev Cancer. 2003 Jun;3(6):453-8
references.pmid: 12778135
references.citation: Biochem Pharmacol. 2012 Jun 15;83(12):1591-601
references.pmid: 22342289
references.citation: Cancer Res. 2004 May 1;64(9):3087-95
references.pmid: 15126345
references.citation: Nature. 2004 Nov 11;432(7014):231-5
references.pmid: 15531879
references.citation: Cancer Res. 2011 Sep 15;71(18):5950-4
references.pmid: 21917736
references.citation: Oncogene. 2007 Jun 28;26(30):4442-52
references.pmid: 17237814
references.citation: Carcinogenesis. 2006 Nov;27(11):2223-34
references.pmid: 16774948
references.citation: J Exp Clin Cancer Res. 2015 Jul 30;34:73
references.pmid: 26223867
references.citation: Nat Med. 2008 Nov;14(11):1271-7
references.pmid: 18931683
references.citation: Oncogene. 2006 Oct 9;25(46):6170-5
references.pmid: 17028596