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Epigenetic regulation of Dlg1, via Kaiso, alters mitotic spindle polarity and promotes intestinal tumourigenesis

Young, Madeleine, May, Stephanie, Damo, Angelos, Young, So Yoon, Man-Wook, Hur, Wojiech, Swat and Parry, Lee 2019. Epigenetic regulation of Dlg1, via Kaiso, alters mitotic spindle polarity and promotes intestinal tumourigenesis. Molecular Cancer Research 17 (3) , pp. 686-696. 10.1158/1541-7786.MCR-18-0280

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Abstract

Both alterations to the epigenome and loss of polarity have been linked to cancer initiation, progression and metastasis. It has previously been demonstrated that loss of the epigenetic reader protein Kaiso suppresses intestinal tumourigenesis in the Apc+/min mouse model, in which altered polarity plays a key role. Thus, we investigated the link between Kaiso deficiency, polarity and suppression of intestinal tumourigenesis. We used Kaiso deficient mice to conditionally delete Apc within the intestinal epithelia and demonstrated up-regulation of the spindle polarity genes Dlg1 and Dlgap1. To understand the role of Dlg1 we generated Villin-creApc+/minDlg1flx/flx Kaiso-/y mice to analyse gene expression, survival, tumour burden and spindle orientation. In vivo analysis of the Dlg1 deficient intestine revealed improper orientation of mitotic spindles and a decreased rate of cellular migration. Loss of Dlg1 decreased survival in Apc+/min mice, validating its role as a tumour suppressor in the intestine. Significantly the increased survival of Apc+/minKaisoy/- mice was shown to be dependent on Dlg1 expression. Taken together this data indicates that maintenance of spindle polarity in the intestinal crypt requires appropriate regulation of Dlg1 expression. As Dlg1 loss leads to incorrect spindle orientation and a delay in cells transiting the intestinal crypt. We propose that the delayed exit from the crypt increases the window in which spontaneous mutations can become fixed, producing a "tumour-permissive" environment, without an increase in mutation rate. Implications: Loss of mitotic spindle polarity delays the exit of cells from the intestinal crypt and promotes a tumourigenic environment.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Biosciences
European Cancer Stem Cell Research Institute (ECSCRI)
Publisher: American Association for Cancer Research
ISSN: 1541-7786
Date of First Compliant Deposit: 1 November 2018
Date of Acceptance: 31 October 2018
Last Modified: 02 Sep 2019 14:23
URI: http://orca.cf.ac.uk/id/eprint/116401

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