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E2F1 Suppresses Wnt&Sol

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E2F1 Suppresses Wnt&Sol Oncogene (2011) 30, 3979–3984 & 2011 Macmillan Publishers Limited All rights reserved 0950-9232/11 www.nature.com/onc SHORT COMMUNICATION E2F1 suppresses Wnt/b-catenin activity through transactivation of b-catenin interacting protein ICAT ZWu1, S Zheng1,ZLi1, J Tan1 and Q Yu1,2 1Department of Cancer Biology and Pharmacology, Genome Institute of Singapore, A*Star (Agency for Science, Technology and Research), Biopolis, Singapore and 2Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore Deregulation of the pRb/E2F or Wnt/b-catenin pathway 2004; Clevers, 2006; Cadigan, 2008; Klaus and Birchmeier, occurs frequently in human cancers, which is often 2008). On the other hand, genetic inactivation of RB associated with inappropriate cell proliferation. Although pathway due to RB mutation or alterations in other the oncogenic roles of pRb/E2F1 and Wnt/b-catenin upstream regulators (such as CyclinD1, Cdk4 or p16) pathways have been well studied, the functional interac- may lead to aberrant activation of another transcription tion between the two pathways has only recently been factor E2F1, leading to deregulation of Rb/E2F1 in a characterized. In particular, E2F1 has been recently variety of human cancers (Sherr and McCormick, 2002). reported to negatively regulate Wnt/b-catenin activity in Unlike Wnt/b-catenin signaling, E2F1 is also equipped human colorectal cancers, though the mechanism under- with an ability to induce apoptosis, suggesting a potential lying this regulation is not fully understood. Here we tumor suppressor function of E2F1. Obviously, the para- provide evidence that b-catenin interacting protein 1 doxical behavior of E2F1 as an oncogene or as a tumor (CTNNBIP1), also known as ICAT (inhibitor of suppressor is operated in a context-dependent manner. b-catenin and TCF4), functions as a crucial node to Compared with other human cancers, a long-standing mediate the cross talk between E2F1 and b-catenin puzzle in most colorectal cancers is the observation that signaling. We show that ICAT is a direct transcriptional while Wnt/b-catenin signaling is activated, E2F1 activity target of E2F1, and that activation of ICAT by E2F1 is is kept at a low level as there are rare mutations in Rb, required for E2F1 to inhibit b-catenin activity. This study as opposed to some 30% inactivation or mutation rate provides a mechanistic insight into the antagonistic of Rb in other human cancers (Nevins, 2001). Moreover, interaction between E2F1 and b-catenin signaling. instead of acting as an oncogene, E2F1 in human Oncogene (2011) 30, 3979–3984; doi:10.1038/onc.2011.129; colorectal cancers may function as a tumor suppressor published online 2 May 2011 and the lower level of E2F1 expression is more correlated with a poor disease outcome (Bramis et al., Keywords: E2F1; Wnt/b-catenin; ICAT; cancer cells 2004). Recently, E2F1 activity in colorectal cancer was reported to be inhibited by CDK8 (Morris et al., 2008), an oncogene amplified in 50% of colorectal cancers (Firestein et al., 2008), leading to activation of b-catenin Introduction activity (Morris et al., 2008). These studies reveal a cross talk between the two critical signaling pathways in colo- Wnt/b-catenin signaling regulates the stability and rectal cancers and further support a tumor suppressor subcellular localization of transcription factor b-catenin role of E2F1 in colorectal cancers by negatively regulat- and therefore b-catenin-dependent gene expression ing b-catenin pathway (Bernards, 2008). Mechanistically, (Logan and Nusse, 2004; Clevers, 2006; Polakis, 2007; several E2F1 targets such as Axin1/2 and SIAH1 have Klaus and Birchmeier, 2008). Deregulation of the Wnt/ been implicated in this process (Firestein et al., 2008; b-catenin pathway has been implicated in human Morris et al., 2008; Xie, 2009). In this study, we seek to malignance, owing to the genetic or epigenetic altera- further understand the mechanistic insights into E2F1 tions in negative or positive regulators of Wnt/b-catenin regulation of Wnt/b-catenin activity and identify b-catenin components, which leads to aberrant activation of its interacting protein 1 (CTNNBIP1), also known as ICAT target genes, such as c-MYC and CyclinD1, promoting (inhibitor of b-catenin and TCF4), as a key E2F1 target cell growth, tissue invasion or metastasis (Moon et al., mediating this effect of E2F1. Correspondence: Dr Q Yu, Department of Cancer Biology and Pharmacology, Genome Institute of Singapore, A*Star (Agency for Results and discussion Science, Technology and Research), Genome, #02-01, 60 Biopolis Street, 138672, Singapore. E-mail: [email protected] E2F1 regulates CTNNBIP1 (ICAT) expression Received 6 February 2011; revised 7 March 2011; accepted 15 March To identify the E2F1 targets that are responsible for 2011; published online 2 May 2011 E2F1-mediated inhibition of Wnt/b-catenin signaling, E2F1 suppresses Wnt/b-catenin activity through ICAT ZWuet al 3980 we used human osteosarcoma Saos-2 cells that express cells resulted in significant induction (X3 fold) of an inducible ER (estrogen receptor)–E2F1 fusion protein. many well-known E2F1 target genes, including CCNA1, In this system, E2F1, which is fused to the hormone- CCNE1/2, BCL2L11, APAF-1, CASP3, CASP9 and binding domain of human estrogen receptor, moves EZH2 (Bracken et al., 2003; Zhao et al., 2005; Iaquinta from the cytoplasm to the nucleus upon addition of and Lees, 2007; Polager and Ginsberg, 2008) in a time- estrogen receptor ligand 4-hydroxytamoxifen (hereafter dependent manner. Consistent with an inhibitory role referred to as OHT) and activates the expression of its of E2F1 on Wnt/b-catenin signaling, we observed the target genes (Vigo et al., 1999). To identify E2F1-regulated downregulation of a number of Wnt/b-catenin target genes, we used the Illumina Huamn Ref-8_V2 Sentrix genes, including CCND1, c-MYC, MMP7, BMP4, BeadChip (Illumina, San Diego, CA, USA) to compare ACCN1 and IL8 (Figure 1a). Among OHT-responsive the transcriptional profile between Saos-2 cells expres- genes, we noticed that CTNNBIP1, which encodes a sing ER-E2F1 and the empty vector (pBabe) that were b-catenin-interacting protein (ICAT), was markedly treated with OHT for 8, 24, or 48 h. As shown in a gene induced in an E2F1-dependent manner (Figure 1a). expression heatmap of representative E2F1-responsive ICAT has been previously reported to inhibit the genes (Figure 1a), OHT treatment of Saos-2 ER-E2F1 interaction of b-catenin with TCF4, leading to the a b d pBabe ER-E2F1 OHT 0 8 24 48 0 8 24 48 h APAF-1 10.0 Saos-2 Saos-2 HCT116 7.5 CASP3 10.0 SIRT1 CCNE1 7.5 CCND3 ICAT 7.5 CCNE1 SIAH1 5.0 mRNA level GAB2 5.0 mRNA level 5.0 MAP3K5 ICAT ICAT EZH2 2.5 2.5 BCL2L11 2.5 CCNA1 Relative Relative Relative mRNA expression CCNE2 0.0 0.0 0.0 DIABLO OHT -+ -+ -+ -+ -+ -+ CHX - - - - + + - - CHX - - - - + + - - CASP9 OHT - + - + - + - + OHT - + - + - + - + AXIN1 pBabe ER-E2F1 WNT1 pBabe ER-E2F1 E132 pBabe ER-E2F1 E132 WNT8B U Up-regulated genes AXIN2 c e WNT4 1.5 ICAT Saos2 ER-E2F1 Saos-2 HCT116 WNT3A WNT8A SIAH1 1.0 WNT9B ACCN1 OHT - + - + - + OHT - + - + - + BMP4 ENC1 0.5 CyclinE1 CyclinE1 ETS2 c-MYC ICAT ICAT genes CCND1 Relativeexpressionm mRNA β-Actin β-Actin MMP7 Down-regulated 0.0 -+ -+ IL8 OHT c-MYC CCND1 -3.0 0 3.0 Figure 1 Ectopic E2F1 upregulates ICAT expression. (a) Gene expression heatmap showing the representative genes that are responsive to E2F1 activation in Saos-2 cells expressing pBabe (vector control) or ER-E2F1. Saos-2 cells infected with a retrovirus expressing ER-E2F1 or an empty vector (pBabe) were treated with OHT (300 nM) for the indicated time points. Total RNA was extracted using TRizol (Invitrogen, Carlsbad, CA, USA) and purified with the RNeasy Mini Kit (Qiagen, Hilden, Germany) according to the manufacturer’s instructions. Reverse transcription was performed using an RNA Amplification kit (Ambion, Austin, TX, USA). The microarray hybridization was performed using the Illumina Gene Expression Sentrix BeadChip HumanRef-8_V2 (Illumina, San Diego, CA, USA), and data analysis was performed and viewed using GeneSpring software from Agilent Technologies (Agilent, Santa Clara, CA, USA). Red, genes with higher expression levels; green, genes with lower expression levels. (b) ICAT, SIAH1 and CCNE1 mRNA expression levels in Saos-2 ER-E2F1 cells upon E2F1 activation. Saos-2 ER-E2F1 or pBabe control cells were treated with OHT (300 nM) for 24 h and the total RNA was isolated as in (a). Quantitative real-time PCR (qRT–PCR) was performed on a PRISM 7900 Sequence Detection System (Applied Biosystems, Carlsbad, CA, USA) using TaqMan probes of ICAT, SIAH1 and CCNE1 (Applied Biosystems). Samples were normalized to the levels of 18S ribosomal RNA. (c) Expression levels of CCND1 and c-MYC, two key Wnt/b-catenin target genes, were downregulated in Saos-2 ER-E2F1 cells upon E2F1 activation. Cell treatment and qRT–PCR were conducted as in (a). (d) ICAT expression levels were determined in pBabe, ER-E2F1 or in mutant ER-E2F1 (E132) systems in both Saos-2 (left) and HCT116 cells in the presence or absence of cycloheximide (10 mg/ml, 8 h). (e) Western blot analysis showing the induction of ICAT and CyclinE1 protein expression in ER-E2F1-expressing Saos-2 (left) or HCT116 (right) cells, but not in pBabe or E132 cells, upon OHT treatment using mouse anti-ICAT (Sigma-Aldrich, St Louis, MO, USA) or anti-CyclinE1 antibody (Santa Cruz, Santa Cruz, CA, USA). b-Actin was used as a loading control. Oncogene E2F1 suppresses Wnt/b-catenin activity through ICAT ZWuet al 3981 ab 25 ICAT 1.2 CCNE1 E2F1 20 ssion ssion ICAT 0.8 15 IMR90/E1A 10 E2F1 siE2F1 -+ 0.4 ICAT E2F1 5 elative mRNA expre elative mRNAexpre CylinE1 ICAT Re R β-Actin 0 β-Actin 0.0 IMR90 IMR90/E1A NC siE2F1 c 20 d Saos-2- Saos2 15 Serum 0 16 24 h E2F1 10 ICAT cells CylinE1 5 β-Actin Peercentage ofS phas 0 0 16 24 h Figure 2 Endogenous E2F1 upregulates ICAT expression.
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