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Role of ZEB1 in Tumor Progression: Regulation of Cell Invasion and Senescence

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Universitat de Barcelona. Facultat de Medicina

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[eng] The members of ZEB family of transcription factors (ZEB1 and ZEB2) are widely known for its role in epithelial-to-mesenchymal transition (EMT), a highly relevant process during development and tumor progression. In this process, cells lose their epithelial features and acquire mesenchymal markers, thus increasing their motility and invasive capacity. However, it has been recently described that ZEB factors can function beyond the EMT induction, and that are associated with other tumor hallmarks: apoptosis inhibition, chemotherapy resistance, etc. Regarding colorectal cancer (CRC), ZEB1 is activated by the Wnt signaling pathway, which is active in around 80% of the cases. Consequently, ZEB1 is expressed in the invasive cells at the tumor front, providing the tumor with higher aggressiveness and metastatic capacity. Taking this background into account, the general aim of the Thesis was to characterize new potential mechanisms through which ZEB1 regulates oncogenic transformation and tumor progression in CRC, beyond EMT induction. The specific aims were: 1) Describe the role of ZEB1 in the regulation of initial steps of tumor invasiveness, such as the remodeling of the extracellular matrix (ECM); 2) Identify new ZEB1 target genes at the tumor front of CRCs, investigating a potential modulation of Wnt signaling, as well as characterizing the in vivo relevance of these potential targets; 3) Identify other hallmarks of cancer that may be regulated by ZEB1 during CRC progression. The results of the Thesis are presented as a summary of publications. The first paper (Clin Cancer Res, 2013. 19(5):1071-82) describes the role of ZEB1 in the opposite regulation of the Plasminogen Activation System (PAS) members (uPA and PAI-1). This regulation promotes the migration of CRC cells through the ECM. The conclusions obtained from this first paper are: 1- ZEB1 modulates CRC cells migration through the peritumoral stroma by means of uPA activation and PAI-1 repression 2- ZEB1 activates uPA at the transcriptional level through its direct binding to the promoter region, in a mechanism involving the coactivator p300 and Wnt signaling. 3- ZEB1 represses PAI-1 by reducing its mRNA stability, which supposes a new gene regulation mechanism for ZEB1. 4- During ZEB1-induced CRC cells migration and invasion, uPA expression is required. 5- ZEB1 correlates positively with uPA, but not with PAI-1, at the invasive front of CRCs, cooperating in its role in ECM remodeling. The results of the second paper (Gut, 2016. doi:10.1136/gutjnl-2015-310838) have identified a new mechanism through which ZEB1 inhibits cancer cells entrance in senescence, a tumor suppressor mechanism. ZEB1 activates the Wnt-antagonnist DKK1, triggering the activation of a signaling cascade that involves mutant p53, MDM2 and CtBP. This ultimate corepressor cooperates with ZEB1 in the repression of macroH2A1, key in senescence induction. The conclusions obtained from this second paper are: 1- The maximum effect of ZEB1 in predicting poor CRC survival requires high Wnt- antagonist DKK1 simultaneous expression. Both genes correlate positively in CRCs. 2- ZEB1 activates DKK1 transcriptionally, through a mechanism that involves the coactivator p300 and the Wnt-effector TCF4. 3- The combined expression of ZEB1 and DKK1 inhibits a senescence-related genes group in CRC patients. Some of these genes, including H2AFY (that codifies for macroH2A1), are cooperatively repressed by ZEB1 and DKK1. 4- ZEB1 requires the presence of DKK1 to repress the formation of senescence- associated heterochromatin foci and the consequent cellular senescence. 5- ZEB1 represses macroH2A1 by direct binding to its promoter. 6- ZEB1 represses cellular senescence through the subsequent activation of DKK1, mutant p53, MDM2 and CtBP. The activation of CtBP enhances ZEB1’s repressor activity on macroH2A1 promoter. 7- ZEB1 correlates positively with DKK1 at CRC tumor front. Conversely, macroH2A1 displays an inverse expression pattern. 8- Reduction of ZEB1 levels in vivo is sufficient to induce senescence, reduce colorectal tumor formation and improve survival in a mouse model of CRC. 9- The tumorigenic capacity of ZEB1 depends on the concomitant low levels of macroH2A1. 10- The role of ZEB1 in determining poor CRC prognosis depends on its ability to repress macroH2A1 and other senescence markers, such as GLB1.

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[cat] Els factors de transcripció ZEB (ZEB1 i ZEB2) son àmpliament coneguts pel seu paper en la transició epitelial-mesenquimal (EMT). A través d’aquest procés, les cèl·lules perden les característiques que les defineixen com a epitelials i adquireixen marcadors mesenquimals, augmentant així la seva capacitat invasiva. Tot i això, recentment s’ha descrit que els factors ZEB tenen funcions més enllà de l’EMT, com ara la resistència a la quimioterapia, que promouen la progressió tumoral. En el cas del càncer colorectal (CCR), s’ha descrit que ZEB1 és activat per la via de senyalització de Wnt, activa en un 80% dels casos. En conseqüència, ZEB1 s’expressa en les cèl·lules invasives del front tumoral. Tenint en compte aquests antecedents, l’objectiu general de la Tesi ha estat el de caracteritzar nous mecanismes a través dels quals ZEB1 regula la transformació oncogènica i la progressió tumoral en CCR, més enllà de la inducció de l’EMT. Els objectius específics han estat: 1) descriure el paper de ZEB1 en la regulació de les etapes inicials d’invasivitat, com la remodelació de la matriu extracel·lular; 2) identificar nous gens diana de ZEB1 al front tumoral de CCR, així com caracteritzar la rellevància d’aquestes dianes in vivo; i 3) identificar processos comuns a tots els tipus de càncer que puguin estar regulades per ZEB1 en la progressió del CCR. Els resultats es presenten com a compendi de publicacions. En el primer dels articles (Clin Cancer Res, 2013. 19(5):1071-82), es descriu el paper de ZEB1 en la regulació oposada dels membres del sistema activador del plasminogen (uPA i PAI-1). Aquesta regulació promou la migració de les cèl·lules a través de la matriu extracel·lular. En el segon dels articles (Gut, 2016. doi:10.1136/gutjnl-2015-310838), s’ha identificat un nou mecanisme a través del qual ZEB1 està inhibint l’entrada de les cèl·lules tumorals a l’estat de senescència, un conegut mecanisme supressor tumoral. ZEB1 activa l’inhibidor de la via Wnt DKK1, desencadenant l’activació d’una ruta de senyalització que implica a p53 mutat, MDM2 i CtBP. Aquest darrer coopera amb ZEB1 en la repressió de la histona macroH2A1, clau en la inducció de la senescència.

# metadata.dc.title[].value
Role of ZEB1 in Tumor Progression: Regulation of Cell Invasion and Senescence