Mbd2 enables tumourigenesis within the intestine while preventing tumour-promoting inflammation

May, S. et al. (2018) Mbd2 enables tumourigenesis within the intestine while preventing tumour-promoting inflammation. Journal of Pathology, 245(3), pp. 270-282. (doi: 10.1002/path.5074) (PMID:29603746) (PMCID:PMC6032908)

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Abstract

Epigenetic regulation plays a key role in the link between inflammation and cancer. Here we examine Mbd2, which mediates epigenetic transcriptional silencing by binding to methylated DNA. In separate studies the Mbd2−/− mouse has been shown (1) to be resistant to intestinal tumourigenesis and (2) to have an enhanced inflammatory/immune response, observations that are inconsistent with the links between inflammation and cancer. To clarify its role in tumourigenesis and inflammation, we used constitutive and conditional models of Mbd2 deletion to explore its epithelial and non‐epithelial roles in the intestine. Using a conditional model, we found that suppression of intestinal tumourigenesis is due primarily to the absence of Mbd2 within the epithelia. Next, we demonstrated, using the DSS colitis model, that non‐epithelial roles of Mbd2 are key in preventing the transition from acute to tumour‐promoting chronic inflammation. Combining models revealed that prior to inflammation the altered Mbd2−/− immune response plays a role in intestinal tumour suppression. However, following inflammation the intestine converts from tumour suppressive to tumour promoting. To summarise, in the intestine the normal function of Mbd2 is exploited by cancer cells to enable tumourigenesis, while in the immune system it plays a key role in preventing tumour‐enabling inflammation. Which role is dominant depends on the inflammation status of the intestine. As environmental interactions within the intestine can alter DNA methylation patterns, we propose that Mbd2 plays a key role in determining whether these interactions are anti‐ or pro‐tumourigenic and this makes it a useful new epigenetic model for inflammation‐associated carcinogenesis.

Item Type:Articles
Additional Information:This work was supported by a Cancer Research UK programme grant. LP is supported by a fellowship from the European Cancer Stem Cell Research Institute. SM is supported by a philanthropic donation from the Mr Lyndon and Mrs Shirley Ann Wood from the Moorhouse Group Ltd. The authors recognise the assistance of lab technicians Sarah Davies, Elaine Tayler, Matt Zverev, Mark Bishop, and Jolene Twomey. AG is supported by a Cancer Research UK Programme grant (C16731/A21200). MS was supported by grants from the German Research Foundation [DFG: KFO257 (sub‐project 4) and FOR 2438 (subproject 2)] and the Interdisciplinary Center for Clinical Research (IZKF) of the Clinical Center Erlangen.
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Sansom, Professor Owen
Authors: May, S., Owen, H., Phesse, T. J., Greenow, K. R., Jones, G.-R., Blackwood, A., Cook, P. C., Towers, C., Gallimore, A. M., Williams, G. T., Stürzl, M., Britzen-Laurent, N., Sansom, O. J., MacDonald, A. S., Bird, A. P., Clarke, A. R., and Parry, L.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
Journal Name:Journal of Pathology
Publisher:Wiley
ISSN:0022-3417
ISSN (Online):1096-9896
Published Online:30 March 2018
Copyright Holders:Copyright © 2018 The Authors
First Published:First published in Journal of Pathology 245(3):270-282
Publisher Policy:Reproduced under a Creative Commons license

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