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Human Homolog of Drosophila Expanded, Hex, Functions As a Putative Tumor Suppressor in Human Cancer Cell Lines Independently of the Hippo Pathway

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Human Homolog of Drosophila Expanded, Hex, Functions As a Putative Tumor Suppressor in Human Cancer Cell Lines Independently of the Hippo Pathway Oncogene (2012) 31, 1189–1195 & 2012 Macmillan Publishers Limited All rights reserved 0950-9232/12 www.nature.com/onc SHORT COMMUNICATION Human homolog of Drosophila expanded, hEx, functions as a putative tumor suppressor in human cancer cell lines independently of the Hippo pathway S Visser-Grieve, Y Hao and X Yang Department of Pathology and Molecular Medicine, Queen’s University, Kingston, Ontario, Canada The Hippo signaling network is proving to be an essential Keywords: expanded; FRMD6; Willin; Hippo; LATS1; regulator within the cell, participating in multiple cellular tumor suppressor phenotypes including cell proliferation, apoptosis, cell migration and organ size control. Much of this pathway is conserved from flies to mammals; however, how the upstream components, namely Expanded, affect down- stream processes in mammalian systems has remained Introduction elusive. Only recently has human Expanded (hEx), also known as FRMD6 or Willin, been identified. However, A mutated expanded (ex) gene was originally identified its functional significance with respect to its putative in 1926 and shown to enhance the growth of imaginal tumor suppressor function and activation of the Hippo discs in Drosophila, suggesting that ex functions as a pathway has not been studied. In this study, we show for tumor suppressor (Stern and Bridges, 1926). Since then, the first time that hEx possesses several tumor suppressor ex has been definitely classified as a tumor suppressor properties. First, hEx dramatically inhibits cell prolifera- due to its abilities to restrict growth, differentiation tion in two human cancer cell lines, MDA-MB-231 and and enhance apoptosis in the wings and eyes of flies MDA-MB-436 cells, and sensitizes these cells to the (Boedigheimer and Laughon, 1993; Blaumueller and chemotherapeutic drug Taxol. Furthermore, downregula- Mlodzik, 2000; McCartney et al., 2000). Due to the tion of hEx in the immortalized MCF10A breast cell line similar overgrowth phenotypes seen in the imaginal leads to enhanced proliferation and resistance to Taxol discs of flies exhibiting mutations in the core Hippo treatment. As evidence for its tumor suppressor function, pathway components, ex was added as a key player in overexpression of hEx inhibits colony formation, soft this pathway (Hamaratoglu et al., 2006). agar colony growth in vitro and in vivo tumor growth in The evolutionarily conserved Hippo signaling path- nude mice. Although Drosophila expanded (ex) can way is an area of intense research due to its fundamental activate the Hippo pathway, surprisingly no significant roles in organ size control and tumorigenesis (Zhao alterations were discovered in the phosphorylation status et al., 2010). In Drosophila, the Ser/Thr kinases Hippo of any of the Hippo pathway components, including (hpo) and dlats along with adapter proteins sav and downstream tumor suppressor LATS1, upon overexpres- mats make up the core components. In this system, sion of hEx. In addition, knockdown of both LATS1 active Hpo phosphorylates and activates dlats, enhanced and LATS2 in hEx-overexpressing cells was unable to by interacting sav and mats. The primary target is Yki, rescue the hEx phenotype, suggesting that hEx functions a transcriptional co-activator and oncogene whose independently of the Hippo pathway in this cell line. Alter- overexpression phenocopies loss of dlats. Several down- natively, we propose a mechanism through which hEx stream targets of Yki have been described, including inhibits progression through the S phase of the cell cycle bantam, cyclin E and diap1. Activation of this pathway by upregulating p21Cip1 and downregulating Cyclin A. This involves the WW and C2-domain containing protein is the first study to functionally characterize hEx and Kibra and two FERM domain proteins ex and mer, show that hEx acts in a distinct manner compared with which all localize to the apical membrane and coopera- Drosophila expanded. tively promote dlats phosphorylation and activation. Oncogene (2012) 31, 1189–1195; doi:10.1038/onc.2011.318; Connecting these membrane-associated proteins with published online 25 July 2011 external growth cues is the atypical cadherin fat or the apical transmembrane protein crumbs, both of which activate ex (reviewed in Pan, 2010 and Halder and Johnson, 2011). Correspondence: Dr X Yang, Department of Pathology and Molecular Importantly, most of this pathway is conserved in Medicine, Queen’s University, Richardson Labs 201, 88 Stuart Street, mammalian systems. Hpo homologs MST1 and MST2 Kingston, Ontario, Canada K7L 3N6. phosphorylate and activate LATS1 and LATS2 (Chan E-mail: [email protected] Received 14 April 2011; revised and accepted 21 June 2011; published et al., 2005). Once activated LATS1/LATS2 bind and online 25 July 2011 phosphorylate the Yki homolog YAP or its paralog hEx functions as a tumor suppressor in human cancer cell lines S Visser-Grieve et al 1190 TAZ, inhibiting their transcriptional activity (Hao et al., 28 WPI ) hEx 2008; Lei et al., 2008). Numerous transcriptional targets 4 24 hEx-shEx for LATS1 and LATS2 (Visser and Yang, 2010a) as well 20 as YAP (Ota and Sasaki, 2008; Zhao et al., 2008) and 16 TAZ (Lai et al., 2011) have been identified with several WPI hEx hEx-shEx 12 hEx (α-FLG) proven to mediate key Hippo pathway functions. 8 Cell number (x10 4 Although this core kinase cascade is well conserved, β-actin 0 upstream regulation of the mammalian Hippo pathway 0 152 3 4 is less understood. Homologs exist for each membrane- Days associated protein: Merlin/NF2 for mer, FRMD6/ 15 Willin/Human Expanded (hEx) for ex, KIBRA for WPI ) hEx Kibra as well as FAT4 for fat and Crumbs1–3 for 4 12 hEx-shEx Crumbs. Although Merlin/NF2 is a well-characterized tumor suppressor and has been shown to enhance 9 LATS1/2 phosphorylation (Lau et al., 2008; Yu et al., WPI hEx hEx-shEx 6 hEx (α-FLG) 2010) and human KIBRA has also been found to bind 3 LATS1 and LATS2 enhancing their phosphorylation Cell number (x10 β -actin 0 and kinase activity (Yu et al., 2010; Xiao et al., 2011), 0 1 2345 thereby functioning in parallel to their Drosophila Days homologs, little is known about hEx in human systems. hEx is a FERM domain protein similar to Merlin pLKO.1 1 60 shEx-1 ) and the ERM (Ezrin, Radixin, Moesin) family of cyto- 4 50 shEx-2 0.8 skeletal crosslinkers and is localized through- 40 out the cytoplasm or along the plasma membrane 0.6 30 (Gunn-Moore et al., 2005). In this study, we outline 0.4 20 the key cellular functions of hEx and suggest that 10 Relative mRNA 0.2 Cell number (x10 hEx possesses tumor suppressor properties. By analyz- 0 ing individual components of the Hippo pathway, 0 0 12345 pLKO.1 shEx-1 shEx-2 we provide the first evidence that hEx does not activate Days or function through this pathway, suggesting that the Figure 1 hEx is a regulator of cell proliferation. (a) Western blot upstream regulation of the Hippo pathway in MDA- analysis of hEx expression levels in MDA-MB-231 cells. Cells were MB-231 cells is not conserved. This study is the first infected with lentivirus expressing vector alone (WPI), hEx-FLG to characterize hEx and provides novel insights into (hEx) or hEx-FLG followed by the subsequent infection with its functions. lentivirus expressing shRNA against hEx (hEx-shEx). Cell lysate extracted from established cell lines was subjected to western blot using anti-FLG M2 monoclonal antibody (Sigma, Oakville, ON, Canada) and b-actin (Sigma) as internal loading control. (b) Cell proliferation analysis. Cells were plated in triplicate with equal cell Results and discussion number into 24-well plates and cell numbers were counted on days 1, 2, 3, 4 and 5 days postplating. Experiments were performed at least three times. Data are mean±s.d. (c) Western blot analysis of To examine the cellular functions of hEx in breast hEx expression in MDA-MB-436 cells. Cell lines establishment and cancer cell lines, we established hEx-expressing MDA- western blot analysis were as described above. (d) Cell proliferation MB-231 cell lines using lentivirus expressing vector analysis was as described for MDA-MB-231 cells. (e) Quantitative alone (WPI) or FLAG-tagged hEx (Figure 1a). MDA- RT–PCR analysis of hEx mRNA levels in MCF10A cells. Cells were infected with lentivirus expressing vector alone (pLKO.1) or MB-231 is an aggressive breast cancer cell line but when expressing one of the two shRNAs targeting hEx (shEx-1 and hEx is overexpressed their growth is severely inhibited shEx-2) (targeting sequences: shEx-1, 50-GATGAAGTTCCAGA (Figure 1b). Importantly, this phenotype is specific to GTTTGTT-30; shEx-2, 50-CCACAGACTATATGTCGGAAA-30). expression of hEx and not due to any non-specific virus mRNA was extracted and qRT–PCR was performed as previously described (Visser and Yang, 2010a) using rRNA as internal effects since knockdown of hEx in the hEx-over- control. (f) Cell proliferation analysis was performed as described expressing cells (hEx-shEx) using lentivirus expressing above. shRNA targeting hEx completely reverses the growth inhibitory phenotype. To show the effect of hEx on cell proliferation is not cell line specific, we repeated these Traditionally, tumor suppressors are defined by their experiments using another aggressive breast cancer cell loss of function in cancer. To recapitulate this in our cell line MDA-MB-436 (Figure 1c). As with the MDA-MB- system we downregulated endogenous hEx in the 231 cells, expression of hEx dramatically inhibits MDA- MCF10A immortalized breast cell line using lentivirus MB-436 cell proliferation whereas the hEx-shEx cell line expressing vector alone (pLKO.1) or one of the two proliferates at a similar rate compared with the WPI shRNAs targeting hEx for degradation (shEx-1 and control cell line (Figure 1d).
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