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Clin Epigenetics. 2018 Sep 26;10(1):120. doi: 10.1186/s13148-018-0548-2.

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

Author information

1
Institute of Pathology, University of Bern, Murtenstrasse 31, Room L310, 3008, Bern, Switzerland.
2
Graduate School for Cellular and Biomedical Sciences, University of Bern, Freiestrasse 1, 3012, Bern, Switzerland.
3
Department of Surgery, Klinikum rechts der Isar, Technische Universität München, Ismaninger Strasse 22, Munich, 81675, Germany.
4
Careanesth AG, Nelkenstrasse 15, Zürich, 8006, Switzerland.
5
Department of Medical Oncology, University Hospital of Bern, 3010, Bern, Switzerland.
6
Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, 90033, CA, USA.
7
Department of Visceral and Internal Medicine, University Hospital of Bern, 3008, Bern, Switzerland.
8
University of Bern and Bürgerspital Solothurn, Schöngrünstrasse 42, 4500, Solothurn, Switzerland.
9
Institute of Pathology, University of Bern, Murtenstrasse 31, Room L310, 3008, Bern, Switzerland. inti.zlobec@pathology.unibe.ch.

Abstract

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 BRAFV600E, 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.

KEYWORDS:

Biomarker; CDX2; Colorectal cancer; Histone modification; Methylation; Prognosis

PMID:
30257705
PMCID:
PMC6158822
DOI:
10.1186/s13148-018-0548-2
[Indexed for MEDLINE]
Free PMC Article

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