Please use this identifier to cite or link to this item: https://ahro.austin.org.au/austinjspui/handle/1/30252
Title: Epithelial de-differentiation triggered by co-ordinate epigenetic inactivation of the EHF and CDX1 transcription factors drives colorectal cancer progression.
Austin Authors: Luk, Ian Y;Jenkins, Laura J;Schoffer, Kael L;Ng, Irvin;Tse, Janson W T;Mouradov, Dmitri;Kaczmarczyk, Stanislaw;Nightingale, Rebecca;Burrows, Allan D;Anderson, Robin L ;Arango, Diego;Dopeso, Higinio;Croft, Larry;Richardson, Mark F;Sieber, Oliver M;Liao, Yang;Mooi, Jennifer K ;Vukelic, Natalia;Reehorst, Camilla M;Afshar-Sterle, Shoukat ;Whitehall, Vicki L J;Fennell, Lochlan;Abud, Helen E;Tebbutt, Niall C ;Phillips, Wayne A;Williams, David S ;Shi, Wei;Mielke, Lisa A;Ernst, Matthias ;Dhillon, Amardeep S;Clemons, Nicholas J;Mariadason, John M 
Affiliation: Olivia Newton-John Cancer Research Institute
Department of Anatomical Pathology, Austin Health, Heidelberg, VIC, Australia
La Trobe University School of Cancer Medicine, Melbourne, VIC, Australia
Department of Medicine, University of Melbourne, Melbourne, VIC, Australia
The University of Queensland, St Lucia, QLD, Australia
Development and Stem Cells Program and the Department of Anatomy and Developmental Biology, Monash Biomedicine Discovery Institute, Monash University, Melbourne, VIC, Australia
Department of Clinical Pathology, University of Melbourne, Parkville, VIC, Australia
School of Computing and Information Systems, University of Melbourne, Parkville, VIC, Australia
The Institute for Mental and Physical Health and Clinical Translation, School of Medicine, Deakin University, Geelong, VIC, Australia
Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
Conjoint Internal Medicine Laboratory, Pathology Queensland, Brisbane, QLD, Australia
QIMR Berghofer Medical Research Institute, Herston, QLD, Australia
Department of Surgery, The University of Melbourne, Parkville, VIC, Australia
Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC, Australia
Department of Medicine, University of Melbourne, Melbourne, VIC, Australia
Personalised Oncology Division, The Walter and Eliza Hall Institute of Medial Research, Parkville, VIC, Australia
Department of Medical Biology, The University of Melbourne, Parkville, VIC, Australia
The Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, VIC, Australia
School of Life and Environmental Sciences, Deakin University, Geelong, VIC, Australia
Group of Biomedical Research in Digestive Tract Tumors, CIBBIM-Nanomedicine, Vall d'Hebron University Hospital Research Institute (VHIR), Barcelona, Spain
Issue Date: 23-May-2022
metadata.dc.date: 2022
Publication information: Cell Death and Differentiation 2022;
Abstract: Colorectal cancers (CRCs) often display histological features indicative of aberrant differentiation but the molecular underpinnings of this trait and whether it directly drives disease progression is unclear. Here, we identify co-ordinate epigenetic inactivation of two epithelial-specific transcription factors, EHF and CDX1, as a mechanism driving differentiation loss in CRCs. Re-expression of EHF and CDX1 in poorly-differentiated CRC cells induced extensive chromatin remodelling, transcriptional re-programming, and differentiation along the enterocytic lineage, leading to reduced growth and metastasis. Strikingly, EHF and CDX1 were also able to reprogramme non-colonic epithelial cells to express colonic differentiation markers. By contrast, inactivation of EHF and CDX1 in well-differentiated CRC cells triggered tumour de-differentiation. Mechanistically, we demonstrate that EHF physically interacts with CDX1 via its PNT domain, and that these transcription factors co-operatively drive transcription of the colonic differentiation marker, VIL1. Compound genetic deletion of Ehf and Cdx1 in the mouse colon disrupted normal colonic differentiation and significantly enhanced colorectal tumour progression. These findings thus reveal a novel mechanism driving epithelial de-differentiation and tumour progression in CRC.
URI: https://ahro.austin.org.au/austinjspui/handle/1/30252
DOI: 10.1038/s41418-022-01016-w
ORCID: 0000-0003-0595-1414
0000-0003-0060-1861
0000-0003-3214-3527
0000-0003-3792-4023
0000-0002-7961-638X
0000-0002-6399-1177
0000-0001-9283-9978
0000-0001-9123-7684
0000-0001-9218-8669
0000-0002-5683-9935
0000-0002-1357-4666
0000-0002-6841-7422
0000-0002-4188-6149
0000-0002-8039-3582
0000-0003-2613-5168
0000-0003-4616-9605
0000-0002-9522-9320
0000-0002-6065-663X
PubMed URL: 35606410
PubMed URL: https://pubmed.ncbi.nlm.nih.gov/35606410/
Type: Journal Article
Appears in Collections:Journal articles

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