The YAP-TEAD4 complex promotes tumor lymphangiogenesis by transcriptionally upregulating CCBE1 in colorectal cancer.
Humans
Calcium-Binding Proteins
/ genetics
Cell Cycle Proteins
/ genetics
Collagen
/ metabolism
Colorectal Neoplasms
/ pathology
Endothelial Cells
/ metabolism
Lymphangiogenesis
/ genetics
Nuclear Proteins
/ genetics
TEA Domain Transcription Factors
Transcription Factors
/ genetics
Tumor Suppressor Proteins
/ genetics
Vascular Endothelial Growth Factor C
/ metabolism
YAP-Signaling Proteins
/ genetics
BET inhibitor
BRD4
CCBE1
TAZ
TEAD4
VEGFC
YAP
colorectal cancer
tumor lymphangiogenesis
Journal
The Journal of biological chemistry
ISSN: 1083-351X
Titre abrégé: J Biol Chem
Pays: United States
ID NLM: 2985121R
Informations de publication
Date de publication:
04 2023
04 2023
Historique:
received:
22
08
2022
revised:
02
02
2023
accepted:
03
02
2023
medline:
28
4
2023
pubmed:
14
2
2023
entrez:
13
2
2023
Statut:
ppublish
Résumé
The secreted protein collagen and calcium-binding EGF domain 1 (CCBE1) is critical for embryonic lymphatic development through its role in the proteolytic activation of mature vascular endothelial growth factor C (VEGFC). We previously reported that CCBE1 is overexpressed in colorectal cancer (CRC) and that its transcription is negatively regulated by the TGFβ-SMAD pathway, but the transcriptional activation mechanism of CCBE1 in CRC remains unknown. Recent studies have revealed the vital role of the hippo effectors YAP/TAZ in lymphatic development; however, the role of YAP/TAZ in tumor lymphangiogenesis has not been clarified. In this study, we found that high nuclear expression of transcription factor TEAD4 is associated with lymph node metastasis and high lymphatic vessel density in patients with CRC. YAP/TAZ-TEAD4 complexes transcriptionally upregulated the expression of CCBE1 by directly binding to the enhancer region of CCBE1 in both CRC cells and cancer-associated fibroblasts, which resulted in enhanced VEGFC proteolysis and induced tube formation and migration of human lymphatic endothelial cells in vitro and lymphangiogenesis in a CRC cell-derived xenograft model in vivo. In addition, the bromodomain and extraterminal domain (BET) inhibitor JQ1 significantly inhibited the transcription of CCBE1, suppressed VEGFC proteolysis, and inhibited tumor lymphangiogenesis in vitro and in vivo. Collectively, our study reveals a new positive transcriptional regulatory mechanism of CCBE1 via YAP/TAZ-TEAD4-BRD4 complexes in CRC, which exposes the protumor lymphangiogenic role of YAP/TAZ and the potential inhibitory effect of BET inhibitors on tumor lymphangiogenesis.
Identifiants
pubmed: 36781122
pii: S0021-9258(23)00144-8
doi: 10.1016/j.jbc.2023.103012
pmc: PMC10124907
pii:
doi:
Substances chimiques
BRD4 protein, human
0
Calcium-Binding Proteins
0
CCBE1 protein, human
0
Cell Cycle Proteins
0
Collagen
9007-34-5
Nuclear Proteins
0
TEA Domain Transcription Factors
0
TEAD4 protein, human
0
Transcription Factors
0
Tumor Suppressor Proteins
0
Vascular Endothelial Growth Factor C
0
YAP1 protein, human
0
YAP-Signaling Proteins
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
103012Informations de copyright
Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article.