CDX2 in colorectal cancer is an independent prognostic factor and regulated by promoter methylation and histone deacetylation in tumors of the serrated pathway.

Graule, Janina; Uth-Gottardi, Kristin; Fischer, Elia Luca; Centeno Ramos, Irene; Galván Hernández, José Alberto; Eichmann, Micha David; Rau, Tilman; Langer, Rupert; Dawson, Heather; Nitsche, Ulrich; Traeger, Peter; Berger, Martin Dave; Schnüriger, Beat; Hädrich, Marion; Studer, Peter; Inderbitzin, Daniel; Lugli, Alessandro; Tschan, Mario; Zlobec, Inti (2018). CDX2 in colorectal cancer is an independent prognostic factor and regulated by promoter methylation and histone deacetylation in tumors of the serrated pathway. Clinical epigenetics, 10(1), p. 120. Springer 10.1186/s13148-018-0548-2

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BACKGROUND In colorectal cancer, CDX2 expression is lost in approximately 20% of cases and associated with poor outcome. Here, we aim to validate the clinical impact of CDX2 and investigate the role of promoter methylation and histone deacetylation in CDX2 repression and restoration. METHODS CDX2 immunohistochemistry was performed on multi-punch tissue microarrays (n = 637 patients). Promoter methylation and protein expression investigated on 11 colorectal cancer cell lines identified two CDX2 low expressors (SW620, COLO205) for treatment with decitabine (DNA methyltransferase inhibitor), trichostatin A (TSA) (general HDAC inhibitor), and LMK-235 (specific HDAC4 and HDAC5 inhibitor). RNA and protein levels were assessed. HDAC5 recruitment to the CDX2 gene promoter region was tested by chromatin immunoprecipitation. RESULTS Sixty percent of tumors showed focal CDX2 loss; 5% were negative. Reduced CDX2 was associated with lymph node metastasis (p = 0.0167), distant metastasis (p = 0.0123), and unfavorable survival (multivariate analysis: p = 0.0008; HR (95%CI) 0.922 (0.988-0.997)) as well as BRAF, mismatch repair deficiency, and CpG island methylator phenotype. Decitabine treatment alone induced CDX2 RNA and protein with values from 2- to 25-fold. TSA treatment ± decitabine also led to successful restoration of RNA and/or protein. Treatment with LMK-235 alone had marked effects on RNA and protein levels, mainly in COLO205 cells that responded less to decitabine. Lastly, decitabine co-treatment was more effective than LMK-235 alone at restoring CDX2. CONCLUSION CDX2 loss is an adverse prognostic factor and linked to molecular features of the serrated pathway. RNA/protein expression is restored in CDX2 low-expressing CRC cell lines by demethylation and HDAC inhibition. Importantly, our data underline HDAC4 and HDAC5 as new epigenetic CDX2 regulators that warrant further investigation.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DBMR Forschung Mu35 > Forschungsgruppe Viszeralchirurgie
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DBMR Forschung Mu35 > Forschungsgruppe Viszeralchirurgie

04 Faculty of Medicine > Department of Gastro-intestinal, Liver and Lung Disorders (DMLL) > Clinic of Visceral Surgery and Medicine > Visceral Surgery
04 Faculty of Medicine > Service Sector > Institute of Pathology > Clinical Pathology
04 Faculty of Medicine > Service Sector > Institute of Pathology
04 Faculty of Medicine > Department of Haematology, Oncology, Infectious Diseases, Laboratory Medicine and Hospital Pharmacy (DOLS) > Clinic of Medical Oncology
04 Faculty of Medicine > Service Sector > Institute of Pathology > Tumour Pathology
04 Faculty of Medicine > Service Sector > Institute of Pathology > Translational Research Unit

Graduate School:

Graduate School for Cellular and Biomedical Sciences (GCB)

UniBE Contributor:

Graule, Janina; Uth-Gottardi, Kristin; Fischer, Elia Luca; Centeno Ramos, Irene; Galván Hernández, José Alberto; Eichmann, Micha David; Rau, Tilman; Langer, Rupert; Dawson, Heather; Berger, Martin Dave; Schnüriger, Beat; Hädrich, Marion; Studer, Peter; Lugli, Alessandro; Tschan, Mario and Zlobec, Inti

Subjects:

500 Science > 570 Life sciences; biology
600 Technology > 610 Medicine & health

ISSN:

1868-7083

Publisher:

Springer

Language:

English

Submitter:

Mario Tschan

Date Deposited:

16 Oct 2018 07:48

Last Modified:

07 Feb 2019 05:45

Publisher DOI:

10.1186/s13148-018-0548-2

PubMed ID:

30257705

Uncontrolled Keywords:

Biomarker CDX2 Colorectal cancer Histone modification Methylation Prognosis

BORIS DOI:

10.7892/boris.120467

URI:

https://boris.unibe.ch/id/eprint/120467

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