Expression of the human antimicrobial peptide β-defensin-1 is repressed by the EGFR-ERK-MYC axis in colonic epithelial cells

The human β-defensin-1 (HBD1) is an antimicrobial peptide constitutively expressed by epithelial cells at mucosal surfaces. In addition to its microbicidal properties, the loss of HBD1 expression in several cancers suggests that it may also have an anti-tumor activity. Here, we investigated the link...

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Bibliographic Details
Published in:	Scientific reports 2018-12, Vol.8 (1), p.18043-12, Article 18043
Main Authors:	Bonamy, Clément, Sechet, Emmanuel, Amiot, Aurélien, Alam, Antoine, Mourez, Michael, Fraisse, Laurent, Sansonetti, Philippe J, Sperandio, Brice
Format:	Article
Language:	eng
Subjects:	Antitumor agents beta-Defensins beta-Defensins - genetics Biochemistry Biochemistry, Molecular Biology Caco-2 Cells Cell Behavior Cells, Cultured Cellular Biology Colon Colon - metabolism Colon cancer Colorectal cancer Colorectal carcinoma Colorectal Neoplasms Colorectal Neoplasms - genetics Colorectal Neoplasms - metabolism Colorectal Neoplasms - pathology Down-Regulation Down-Regulation - genetics Epidermal growth factor Epidermal growth factor receptors Epithelial Cells Epithelial Cells - metabolism ErbB Receptors ErbB Receptors - physiology Extracellular signal-regulated kinase Extracellular Signal-Regulated MAP Kinases Extracellular Signal-Regulated MAP Kinases - metabolism Gene Expression Regulation, Neoplastic Genomics HT29 Cells Humans Intestinal Mucosa Intestinal Mucosa - metabolism Life Sciences MAP Kinase Signaling System MAP Kinase Signaling System - physiology Microbicides Molecular biology Molecular Networks Mucosa Myc protein Organoids Peptides Proto-Oncogene Proteins c-myc Proto-Oncogene Proteins c-myc - physiology Signal Transduction Signal Transduction - genetics Subcellular Processes Transcription Tumor cell lines
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Summary:	The human β-defensin-1 (HBD1) is an antimicrobial peptide constitutively expressed by epithelial cells at mucosal surfaces. In addition to its microbicidal properties, the loss of HBD1 expression in several cancers suggests that it may also have an anti-tumor activity. Here, we investigated the link between HBD1 expression and cancer signaling pathways in the human colon cancer cell lines TC7 and HT-29, and in normal human colonic primary cells, using a mini-gut organoid model. Using available datasets from patient cohorts, we found that HBD1 transcription is decreased in colorectal cancer. We demonstrated that inhibiting the Epidermal Growth Factor Receptor (EGFR) increased HBD1 expression, whereas activating EGFR repressed HBD1 expression, through the MEKK1/2-ERK1/2 pathway that ultimately regulates MYC. We finally present evidences supporting a role of MYC, together with the MIZ1 coregulator, in HBD1 regulation. Our work uncovers the role and deciphers the function of the EGFR-ERK-MYC axis as a repressor of HBD1 expression and contributes to the understanding of HBD1 suppression observed in colorectal cancer.
ISSN:	2045-2322 2045-2322