A novel miR-193a-5p-YY1-APC regulatory axis in human endometrioid endometrial adenocarcinoma.
Aberrant expression and altered function of transcription factors (TFs) have vital roles in many aspects of tumor development and progression. In this study, we investigated the functional significance of a TF, Yin Yang1 (YY1) in tumorigenesis of endometrioid endometrial carcinoma (EEC). We demonstrated that YY1 is upregulated in EEC cell lines and primary tumors; and its expression is associated with tumor stages. Depletion of YY1 inhibits EEC cell proliferation and migration both in vitro and in vivo, whereas overexpression of YY1 promotes EEC cell growth. These results suggest that YY1 functions as an oncogenic factor in EEC. Transcriptome analysis revealed a significant effect of YY1 on critical aspects of EEC tumorigenesis through inhibition of APC expression. Further mechanistic investigation uncovered a new epigenetic silencing mode of APC by YY1 through recruitment of EZH2 and trimethylation of histone 3 lysine 27 on its promoter region. Moreover, YY1 overexpression was found to be a consequence of miR-193a-5p downregulation through direct miR-193a-5p-YY1 interplay. Our results therefore establish a novel miR-193a-5p-YY1-APC axis, which contributes to EEC development, and may serve as future intervention target.
Department of Obstetrics and Gynaecology, The Chinese University of Hong Kong, Hong Kong SAR, China.
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Yang
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Zhou
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Lu
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Wang
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Li
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Jiang
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Chan
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Zhang
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Yu
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Kwong
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Cheung
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Chung
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Mak
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Sun
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Wang
D025601:Adenomatous Polyposis Coli Protein / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D018269:Carcinoma, Endometrioid / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D016889:Endometrial Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D020868:Gene Silencing; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D056484:Jumonji Domain-Containing Histone Demethylases / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology; D023041:Xenograft Model Antitumor Assays; D050986:YY1 Transcription Factor / Q000235:genetics* / Q000378:metabolism
C555337:APC protein, human; D025601:Adenomatous Polyposis Coli Protein; C546818:MIRN193 microRNA, human; D035683:MicroRNAs; D050986:YY1 Transcription Factor; C494698:YY1 protein, human; D056484:Jumonji Domain-Containing Histone Demethylases; C523761:Kdm6b protein, mouse