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Transcriptional Regulation of Cell Polarity in EMT and Cancer

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Transcriptional Regulation of Cell Polarity in EMT and Cancer Oncogene (2008) 27, 6958–6969 & 2008 Macmillan Publishers Limited All rights reserved 0950-9232/08 $32.00 www.nature.com/onc REVIEW Transcriptional regulation of cell polarity in EMT and cancer G Moreno-Bueno, F Portillo and A Cano Departamento de Bioquı´mica, Universidad Auto´noma de Madrid, Instituto de Investigaciones Biome´dicas ‘Alberto Sols’, Consejo Superior de Investigaciones Cientı´ficas-Universidad Auto´noma de Madrid, Madrid, Spain The epithelial-to-mesenchymal transition (EMT) is a can lead primary tumours to metastasize (Thiery, 2003; crucial process in tumour progression providing tumour Gupta and Massague´ , 2006).EMT is typically chara- cells with the ability to escape from the primary tumour, cterized by the loss of cell–cell adhesion and apical– to migrate to distant regions and to invade tissues. EMT basal cell polarity, as well as the increased motility of requires a loss of cell–cell adhesion and apical–basal cells (Thiery, 2003).Cell adhesion and polarity in polarity,as well as the acquisition of a fibroblastoid motile epithelia depends on the formation of adherens junc- phenotype. Several transcription factors have emerged in tions in which E-cadherin is a key determinant, recent years that induce EMT,with important implica- providing the physical structure for both cell–cell tions for tumour progression. However,their effects on attachment and the recruitment of signalling complexes cell polarity remain unclear. Here,we have re-examined (reviewed by Knust and Bossinger, 2002; Perez-Moreno the data available related to the effect of EMT related et al., 2003). One of the earliest steps in EMT is the loss transcription factors on epithelial cell plasticity,focusing of E-cadherin function, and in fact it is generally on their impact on cell polarity. Transcriptional and accepted that EMT-inducing factors initiate epithelial post-transcriptional regulatory mechanisms mediated by reorganization by impairing the expression or function several inducers of EMT,in particular the ZEB and of E-cadherin (Peinado et al., 2004; Jeanes et al., 2008). Snail factors,downregulate the expression and/or func- The characterization of E-cadherin regulation during tional organization of core polarity complexes. We also EMT has provided important insights into the mole- summarize data on the expression of cell polarity cular mechanisms involved in the loss of cell–cell genes in human tumours and analyse genetic interactions adhesion and in the acquisition of migratory properties that highlight the existence of complex regulatory net- during carcinoma progression (Peinado et al., 2007). To works converging on the regulation of cell polarity by date, many different extracellular cues have been shown EMT inducers in human breast carcinomas. These to trigger epithelial dedifferentiation and EMT, such as recent observations provide new insights into the relation- those involving transforming growth factor-b (TGF-b), ship between alterations in cell polarity components Notch, fibroblast growth factor and Wnt signalling and EMT in cancer,opening new avenues for their pathways (Barrallo-Gimeno and Nieto, 2005; De Craene potential use as therapeutic targets to prevent tumour et al., 2005a; Huber et al., 2005; Thiery and Sleeman, progression. 2006).Most of the signals inducing EMT exert their Oncogene (2008) 27, 6958–6969; doi:10.1038/onc.2008.346 action through the modulation of transcription factors that repress epithelial genes, such as those encoding Keywords: cell polarity; EMT; Snail; ZEB; tumour E-cadherin and cytokeratins, and that activate markers; interacting networks transcription programmes that specify fibroblast-like motility and an invasive phenotype (Thiery and Sleeman, 2006; Peinado et al., 2007). Several transcription factors have been said to drive EMT, including members of the Snail and basic Helix Loop Helix (bHLH) families, and two double zinc finger Introduction and homeodomain (ZEB) factors (reviewed by Peinado et al., 2007). Extensive analysis of such transcription Metastasis is the most important cause of morbidity and factors has clearly demonstrated their implication in the mortality in human cancers.The epithelial-to-mesench- loss of cell–cell adhesion and in gaining motility, ymal transition (EMT) is an essential process during although an analysis of their impact on cell polarity is embryogenesis (Barrallo-Gimeno and Nieto, 2005) and still pending.Here, we have re-examined the existing its pathological activation during tumour development data on the effect and relationship of the EMT transcription factors on epithelial cell plasticity, focusing our attention on their impact on cell polarity Correspondence: Professor A Cano, Instituto de Investigaciones Biome´ dicas ‘Alberto Sols’ CSIC-UAM, Arturo Duperier 4, Madrid mechanisms.We also summarize the data available 28029, Spain. on the expression of cell polarity genes and their E-mail: [email protected] transcriptional regulators in human tumours, which Polarity regulation in EMT G Moreno-Bueno et al 6959 highlight the existence of complex regulatory networks The assembly and localization of the apical junctional that converge on the regulation of cell polarity in complex require a set of conserved polarity-generating tumours.Apart from their potential as new tumour protein complexes.To date, three core interacting markers, the existence of complex networks involving protein complexes have been identified in mammals EMT regulators that control cell polarity is becoming that participate in apical–basal cell polarity and that evident. influence the assembly and localization of the junctional complexes: (1) the PAR (Par6/Par3/atypical protein kinase C (aPKC)) complex; (2) the CRB (Crb/Pals/Patj) Polarity-generating protein complexes at a glance complex; and (3) the SCRIB (Scrib/Dlg/Lgl) complex (reviewed by Dow and Humbert, 2007; Assemat et al., Although our present understanding of the protein 2008; Aranda et al., 2008; Humbert et al., 2008).The complexes involved in the generation of polarity has PAR complex was initially identified in Caenorabditis been dealt with in more specialized reviews (Dow and elegans mutants (for partitioned defective; Kemphues Humbert, 2007; Lee and Vasioukhin, 2008), to under- et al., 1988), and in mammals, it is composed of two stand the significance of the alteration in the expression scaffold proteins (PAR6 and PAR3) and an aPKC.To of cell polarity genes during tumour development, we date, two PAR3 (PARD3, PARD3B), three PAR6 will briefly summarize the epithelial cell polarity (PARD6A, PARD6B, PARD6G) and two aPKC systems.Epithelial cells maintain two types of cell (PRKCI, PRKCZ) genes have been identified in polarity, planar and apical–basal polarity (Dow and mammalian genomes.The PAR complex is localized Humbert, 2007).Planar polarity is the polarization of to the apical junction domain, and significant evidence cells across the two dimensions of the epithelial sheet indicates that it has an important function in the and it will not be considered here (reviewed by Zallen, assembly of tight junctions (reviewed by Goldstein and 2007).The apical–basal polarity of epithelial cells in an Macara, 2007; Ebnet, 2008).The CRB and SCRIB epithelium is evident from the presence of two specia- complexes were initially identified in Drosophila mela- lized plasma membrane domains, the apical surface nogaster when screening mutations responsible for facing the lumen and a basolateral surface that contacts epithelial defects (reviewed by Assemat et al., 2008). the adjacent cells and the underlying connective tissue. Mammalian CRB complex localizes to the apical Apical–basal polarity may also be present in multilayer membrane and are made up of the transmembrane epithelial tissues, but in this case, the apical cell surface protein Crumbs (Crb) and the cytoplasmic scaffolding is in contact with the upper epithelial layer.The proteins PALS1 (the homologue of Drosophila Stardust, asymmetrical distribution of lipids and proteins between Sdt, a MAGUK protein) and PATJ (Pals-associated both apical and basal domains reflects their different tight junction protein, the homologue of Dpatj).At functions, and it is the result of both polarized present, there are three CRB, two Pals and one PATJ trafficking and the presence of a physical frontier gene known to exist in humans (Assemat et al., 2008). established by the apical junctional complex comprised The composition and function of the CRB complex in of tight junctions and adherens junctions.Tight junc- the mammalian retina have been recently reviewed tions provide a tight seal between neighbouring cells, (Gosens et al., 2008), where mutations in the human which is essential for the epithelium to function as a CRB1 gene cause autosomal recessive retinitis pigmen- barrier, whereas adherens junctions maintain the adhe- tosa and autosomal Leber congenital amaurosis (Ri- sion between neighbouring cells.The protein composi- chard et al., 2006). The mammalian SCRIB complex is tion and barrier properties of this apical junctional localized in the basolateral domain of epithelial cells and complex have recently been reviewed (Perez-Moreno it is comprised of three proteins, Scribble (Scrib), Disc et al., 2003; Perez-Moreno and Fuchs, 2006; Niessen, large (Dlg) and Lethal giant larvae (Lgl) (reviewed by 2007; Hartsock and Nelson, 2008).As such, tight and Vasioukhin, 2006).Four DLG (DLG1-4) and two LGL adherens junctions are composed of transmembrane (LGL1, LGL2) have now been identified in the proteins that adhere to similar
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