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Journal of Cancer Research and Clinical Oncology

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01-11-2017 | Original Article - Cancer Research

EZH2 is involved in silencing of WNT5A during epithelial–mesenchymal transition of colon cancer cell line

Authors: Jianxin Tao, Liping Shi, Longchang Huang, Haoze Shi, Hang Chen, Yixin Wang, Tong Wang

Published in: Journal of Cancer Research and Clinical Oncology | Issue 11/2017

Abstract

Purpose

Transforming growth factor-β (TGF-β) induction of epithelial–mesenchymal transition (EMT) in SW480 was established as a system for studies of colon cancer metastasis. However, the epigenetic mechanisms underlying this process remain unknown. In mammal, polycomb repressive complex-2 (PRC2) is a highly conserved histone methyltransferase involved in epigenetic regulations. Enhancer of zeste Homolog 2 (EZH2) is the catalytic subunit of PRC2, which catalyzes methylation of lysine 27 of histone H3 (H3K27).

Methods

An inducible EMT system in colorectal cancer was utilized to study its mechanistic and phenotypic changes. Particularly, gene expression analysis was studied after immunoprecipitation.

Results

In this study, we reported that EZH2 is significantly enriched in the promoter region of WNT5A after TGF-β induction in SW480 colon cancer cell line, which in turn silenced the expression of WNT5A. Furthermore, EZH2 inhibitor antagonized the TGF-β-induced morphological conversion associated with epithelial–mesenchymal transition (EMT). Conversely, inhibition of histone H3K27me3 reader CBX does not affect the WNT5A expression level during TGF-β-induced EMT.

Conclusions

Our results indicate that EZH2 was essential for the silencing of WNT5A during TGF-β-induced epithelial–mesenchymal transition of colon cancer cells.

Aranda S, Mas G, Di Croce L (2015) Regulation of gene transcription by polycomb proteins. Sci Adv 1:e1500737. doi:10.1126/sciadv.1500737 CrossRefPubMedPubMedCentral

Asem MS, Buechler S, Wates RB, Miller DL, Stack MS (2016) Wnt5a signaling in cancer. Cancers (Basel) 8:79. doi:10.3390/cancers8090079 CrossRef

Bierne H et al (2009) Human BAHD1 promotes heterochromatic gene silencing. Proc Natl Acad Sci USA 106:13826–13831. doi:10.1073/pnas.0901259106 CrossRefPubMedPubMedCentral

Bo H, Zhang S, Gao L, Chen Y, Zhang J, Chang X, Zhu M (2013) Upregulation of Wnt5a promotes epithelial-to-mesenchymal transition and metastasis of pancreatic cancer cells. BMC Cancer 13:496. doi:10.1186/1471-2407-13-496 CrossRefPubMedPubMedCentral

Brunen D, Willems SM, Kellner U, Midgley R, Simon I, Bernards R (2013) TGF-beta: an emerging player in drug resistance. Cell Cycle 12:2960–2968. doi:10.4161/cc.26034 CrossRefPubMedPubMedCentral

Cadigan KM, Nusse R (1997) Wnt signaling: a common theme in animal development. Genes Dev 11:3286–3305CrossRefPubMed

Cheng R, Sun B, Liu Z, Zhao X, Qi L, Li Y, Gu Q (2014) Wnt5a suppresses colon cancer by inhibiting cell proliferation and epithelial–mesenchymal transition. J Cell Physiol 229:1908–1917. doi:10.1002/jcp.24566 CrossRefPubMed

Chi P, Allis CD, Wang GG (2010) Covalent histone modifications-miswritten, misinterpreted and mis-erased in human cancers. Nat Rev Cancer 10:457–469. doi:10.1038/nrc2876 CrossRefPubMedPubMedCentral

Dissanayake SK et al (2007) The Wnt5A/protein kinase C pathway mediates motility in melanoma cells via the inhibition of metastasis suppressors and initiation of an epithelial to mesenchymal transition. J Biol Chem 282:17259–17271. doi:10.1074/jbc.M700075200 CrossRefPubMedPubMedCentral

Hansen KH et al (2008) A model for transmission of the H3K27me3 epigenetic mark. Nat Cell Biol 10:1291–1300. doi:10.1038/ncb1787 CrossRefPubMed

Jiang G, Lin J, Wang W, Sun M, Chen K, Wang F (2017) WNT5A promoter methylation is associated with better responses and longer progression-free survival in colorectal cancer patients treated with 5-fluorouracil-based chemotherapy. Genet Test Mol Biomark 21:74–79. doi:10.1089/gtmb.2016.0162 CrossRef

Jin J et al (2016) Prognostic value of wingless-type proteins in non-small cell lung cancer patients: a meta-analysis. Transl Lung Cancer Res 5:436–442. doi:10.21037/tlcr.2016.08.08 CrossRefPubMedPubMedCentral

Kanzawa M, Semba S, Hara S, Itoh T, Yokozaki H (2013) WNT5A is a key regulator of the epithelial–mesenchymal transition and cancer stem cell properties in human gastric carcinoma cells. Pathobiology 80:235–244. doi:10.1159/000346843 CrossRefPubMed

Kim J, Kim H (2012) Recruitment and biological consequences of histone modification of H3K27me3 and H3K9me3. ILAR J 53:232–239. doi:10.1093/ilar.53.3-4.232 CrossRefPubMedPubMedCentral

Kim KH, Roberts CW (2016) Targeting EZH2 in cancer. Nat Med 22:128–134. doi:10.1038/nm.4036 CrossRefPubMedPubMedCentral

Kremenevskaja N, von Wasielewski R, Rao AS, Schofl C, Andersson T, Brabant G (2005) Wnt-5a has tumor suppressor activity in thyroid carcinoma. Oncogene 24:2144–2154. doi:10.1038/sj.onc.1208370 CrossRefPubMed

Li Q, Chen H (2012) Silencing of Wnt5a during colon cancer metastasis involves histone modifications. Epigenetics 7:551–558. doi:10.4161/epi.20050 CrossRefPubMedPubMedCentral

Li J et al (2010) WNT5A antagonizes WNT/beta-catenin signaling and is frequently silenced by promoter CpG methylation in esophageal squamous cell carcinoma. Cancer Biol Ther 10:617–624CrossRefPubMed

Luo H et al (2016) EZH2 promotes invasion and metastasis of laryngeal squamous cells carcinoma via epithelial–mesenchymal transition through H3K27me3. Biochem Biophys Res Commun 479:253–259. doi:10.1016/j.bbrc.2016.09.055 CrossRefPubMed

Margueron R, Reinberg D (2011) The polycomb complex PRC2 and its mark in life. Nature 469:343–349. doi:10.1038/nature09784 CrossRefPubMedPubMedCentral

McCabe MT et al (2012) EZH2 inhibition as a therapeutic strategy for lymphoma with EZH2-activating mutations. Nature 492:108–112. doi:10.1038/nature11606 CrossRefPubMed

Pino MS et al (2010) Epithelial to mesenchymal transition is impaired in colon cancer cells with microsatellite instability. Gastroenterology 138:1406–1417. doi:10.1053/j.gastro.2009.12.010 CrossRefPubMed

Prasad CP, Chaurasiya SK, Guilmain W, Andersson T (2016) WNT5A signaling impairs breast cancer cell migration and invasion via mechanisms independent of the epithelial–mesenchymal transition. J Exp Clin Cancer Res 35:144. doi:10.1186/s13046-016-0421-0 CrossRefPubMedPubMedCentral

Qi H et al (2014) Wnt5a promotes vasculogenic mimicry and epithelial–mesenchymal transition via protein kinase Calpha in epithelial ovarian cancer. Oncol Rep 32:771–779. doi:10.3892/or.2014.3229 CrossRefPubMed

Ren X, Vincenz C, Kerppola TK (2008) Changes in the distributions and dynamics of polycomb repressive complexes during embryonic stem cell differentiation. Mol Cell Biol 28:2884–2895. doi:10.1128/MCB.00949-07 CrossRefPubMedPubMedCentral

Roman-Gomez J et al (2007) WNT5A, a putative tumour suppressor of lymphoid malignancies, is inactivated by aberrant methylation in acute lymphoblastic leukaemia. Eur J Cancer 43:2736–2746. doi:10.1016/j.ejca.2007.10.004 CrossRefPubMed

Simon JA, Lange CA (2008) Roles of the EZH2 histone methyltransferase in cancer epigenetics. Mutat Res 647:21–29. doi:10.1016/j.mrfmmm.2008.07.010 CrossRefPubMed

Stuckey JI et al (2016) A cellular chemical probe targeting the chromodomains of Polycomb repressive complex 1. Nat Chem Biol 12:180–187. doi:10.1038/nchembio.2007 CrossRefPubMedPubMedCentral

Verma SK et al (2012) Identification of potent, selective, cell-active inhibitors of the histone lysine methyltransferase EZH2. ACS Med Chem Lett 3:1091–1096. doi:10.1021/ml3003346 CrossRefPubMedPubMedCentral

Wang Z, Chen H (2010) Genistein increases gene expression by demethylation of WNT5a promoter in colon cancer cell line SW1116. Anticancer Res 30:4537–4545PubMed

Ying J et al (2008) WNT5A exhibits tumor-suppressive activity through antagonizing the Wnt/beta-catenin signaling, and is frequently methylated in colorectal cancer. Clin Cancer Res 14:55–61. doi:10.1158/1078-0432.CCR-07-1644 CrossRefPubMed

Zhan T, Rindtorff N, Boutros M (2017) Wnt signaling in cancer. Oncogene 36:1461–1473. doi:10.1038/onc.2016.304 CrossRefPubMed

Zhang Y, Li Q, Chen H (2013) DNA methylation and histone modifications of Wnt genes by genistein during colon cancer development. Carcinogenesis 34:1756–1763. doi:10.1093/carcin/bgt129 CrossRefPubMedPubMedCentral

Zhang T, Cooper S, Brockdorff N (2015) The interplay of histone modifications—writers that read. EMBO Rep 16:1467–1481. doi:10.15252/embr.201540945 CrossRefPubMedPubMedCentral

Zhao D, Zhang X, Guan H, Xiong X, Shi X, Deng H, Li H (2016) The BAH domain of BAHD1 is a histone H3K27me3 reader. Protein Cell 7:222–226. doi:10.1007/s13238-016-0243-z CrossRefPubMedPubMedCentral

Title: EZH2 is involved in silencing of WNT5A during epithelial–mesenchymal transition of colon cancer cell line
Authors: Jianxin Tao
Liping Shi
Longchang Huang
Haoze Shi
Hang Chen
Yixin Wang
Tong Wang
Publication date: 01-11-2017
Publisher: Springer Berlin Heidelberg
Published in: Journal of Cancer Research and Clinical Oncology / Issue 11/2017
Print ISSN: 0171-5216
Electronic ISSN: 1432-1335
DOI: https://doi.org/10.1007/s00432-017-2479-2

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EZH2 is involved in silencing of WNT5A during epithelial–mesenchymal transition of colon cancer cell line

Abstract

Purpose

Methods

Results

Conclusions

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Abstract

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