title: Role of STAT3 and vitamin D receptor in EZH2-mediated invasion of human colorectal cancer.
abstract: The polycomb group protein enhancer of zeste homologue 2 (EZH2), which has histone methyltransferase (HMT) activity, is overexpressed in malignant tumours. However, the role of EZH2 in colorectal cancer (CRC) invasion is little known. Here we investigated the clinical significance, biological effects, and mechanisms of EZH2 signalling. Knockdown of EZH2 significantly reduced cell invasion and secretion of matrix metalloproteinases 2/9 (MMP2/9) in in vitro studies. Knockdown of EZH2 dramatically increased overall survival and decreased metastasis of lung in in vivo studies. Conversely, overexpression of EZH2 significantly increased lung metastasis and shortened overall survival when compared with control tumours. EZH2-induced CRC cell invasion may depend on down-regulation of vitamin D receptor (VDR), which is considered to be a marker of CRC invasion. EZH2 regulates the histone trimethylation of lysine 27 (H3K27me3) in the VDR promoter. Moreover, we found that STAT3 directly binds to the EZH2 promoter and regulates VDR down-regulation in CRC cells. Significant inverse correlations were observed between the expression of EZH2 and pSTAT3 and that of VDR in CRC tissues compared with normal tissue in patients. We show the role of EZH2 in CRC metastasis and identify VDR as a target gene of EZH2. EZH2 expression may be directly regulated by STAT3, and STAT3 may play an important role in EZH2-mediated VDR down-regulation in CRC. This pathway may provide potential targets in aggressive CRC.
authors: Division of Gastroenterology and Hepatology, Renji Hospital, Shanghai Institution of Digestive Disease, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory of Oncogene and Related Genes, Shanghai Jiao-Tong University School of Medicine, 145 Middle Shandong Road, Shanghai, 200001, China.
authors: Yan-Wei
authors: YW
authors: Lin
authors: Lin-Lin
authors: LL
authors: Ren
authors: Hua
authors: H
authors: Xiong
authors: Wan
authors: W
authors: Du
authors: Ya-Nan
authors: YN
authors: Yu
authors: Tian-Tian
authors: TT
authors: Sun
authors: Yu-Rong
authors: YR
authors: Weng
authors: Zhen-Hua
authors: ZH
authors: Wang
authors: Ji-Lin
authors: JL
authors: Wang
authors: Ying-Chao
authors: YC
authors: Wang
authors: Yun
authors: Y
authors: Cui
authors: Dan-Feng
authors: DF
authors: Sun
authors: Ze-Guang
authors: ZG
authors: Han
authors: Nan
authors: N
authors: Shen
authors: Weiping
authors: W
authors: Zou
authors: Jie
authors: J
authors: Xu
authors: Hao-Yan
authors: HY
authors: Chen
authors: Weibiao
authors: W
authors: Cao
authors: Jie
authors: J
authors: Hong
authors: Jing-Yuan
authors: JY
authors: Fang
mesh_terms: D000818:Animals; D001483:Base Sequence; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D015536:Down-Regulation; D000071221:Enhancer of Zeste Homolog 2 Protein; D015972:Gene Expression Regulation, Neoplastic; D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics / Q000378:metabolism; D006657:Histones / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008239:Lysine / Q000378:metabolism; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D008745:Methylation; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008969:Molecular Sequence Data; D009361:Neoplasm Invasiveness; D063151:Polycomb Repressive Complex 2 / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D018167:Receptors, Calcitriol / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D006657:Histones; D018167:Receptors, Calcitriol; D011993:Recombinant Fusion Proteins; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C579457:VDR protein, human; D000076983:Histone Methyltransferases; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D011495:Histone-Lysine N-Methyltransferase; D063151:Polycomb Repressive Complex 2; C522361:MMP2 protein, human; D020778:Matrix Metalloproteinase 2; C579270:MMP9 protein, human; D020780:Matrix Metalloproteinase 9; D008239:Lysine