E-cadherin is transcriptionally activated via suppression of ZEB1 transcriptional repressor by small RNA-mediated gene silencing.
RNA activation has been reported to be induced by small interfering RNAs (siRNAs) that act on the promoters of several genes containing E-cadherin. In this study, we present an alternative mechanism of E-cadherin activation in human PC-3 cells by siRNAs previously reported to possess perfect-complementary sequences to E-cadherin promoter. We found that activation of E-cadherin can be also induced via suppression of ZEB1, which is a transcriptional repressor of E-cadherin, by seed-dependent silencing mechanism of these siRNAs. The functional seed-complementary sites of the siRNAs were found in the coding region in addition to the 3' untranslated region of ZEB1 mRNA. Promoter analyses indicated that E-boxes, which are ZEB1-binding sites, in the upstream promoter region are indispensable for E-cadherin transcription by the siRNAs. Thus, the results caution against ignoring siRNA seed-dependent silencing effects in genome-wide transcriptional regulation. In addition, members of miR-302/372/373/520 family, which have the same seed sequences with one of the siRNAs containing perfect-complementarity to E-cadherin promoter, are also found to activate E-cadherin transcription. Thus, E-cadherin could be upregulated by the suppression of ZEB1 transcriptional repressor by miRNAs in vivo.
Department of Biophysics and Biochemistry, Graduate School of Science, University of Tokyo, Tokyo, Japan.
Minami
M
Mazda
Kenji
K
Nishi
Yuki
Y
Naito
Kumiko
K
Ui-Tei
D001483:Base Sequence; D015820:Cadherins / Q000235:genetics*; D045744:Cell Line, Tumor; D015536:Down-Regulation / Q000235:genetics; D020868:Gene Silencing; D057809:HEK293 Cells; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D035683:MicroRNAs / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D011401:Promoter Regions, Genetic / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics*; D014157:Transcription Factors / Q000172:deficiency* / Q000235:genetics* / Q000378:metabolism; D015533:Transcriptional Activation / Q000235:genetics*; D059467:Transcriptome / Q000235:genetics; D015854:Up-Regulation / Q000235:genetics; D000071799:Zinc Finger E-box-Binding Homeobox 1
D015820:Cadherins; D018398:Homeodomain Proteins; D035683:MicroRNAs; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D014157:Transcription Factors; C486307:ZEB1 protein, human; D000071799:Zinc Finger E-box-Binding Homeobox 1