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Reciprocal activation of HEY1 and NOTCH4 under SOX2 control promotes EMT in head and neck squamous cell carcinoma.
- Source :
-
International journal of oncology [Int J Oncol] 2021 Feb; Vol. 58 (2), pp. 226-237. Date of Electronic Publication: 2020 Dec 10. - Publication Year :
- 2021
-
Abstract
- Several comprehensive studies have demonstrated that the NOTCH pathway is altered in a bimodal manner in head and neck squamous cell carcinoma (HNSCC). In a previous study, it was found that the NOTCH4/HEY1 pathway was specifically upregulated in HNSCC and promoted epithelial‑mesenchymal transition (EMT), and that HEY1 activation supported SOX2 expression. However, the interactions in this pathway have not yet been fully elucidated. The present study investigated the NOTCH4/HEY1/SOX2 axis in HNSCC using in vitro models and the Cancer Genome Atlas (TCGA) database. To explore the association, reporter and ChIP RT‑qPCR assays using SOX2‑overexpressing (SOX2‑OE) cells were performed. The association between NOTCH4 and HEY1 was examined in the same manner using HEY1‑overexpressing (HEY1‑OE) cells. The results of the in vitro experiments indicated that HEY1 promoted EMT in the HNSCC cells. Furthermore, the overexpression of HEY1 also promoted sphere formation and increased murine xenograft tumorigenicity. Reporter assays and ChIP RT‑qPCR experiments indicated that SOX2 regulated HEY1 expression via direct binding of the HEY1 promoter. HEY1 expression significantly correlated with SOX2 expression in primary lung SCC and other SCCs using the TCGA database. HEY1 also regulated NOTCH4 expression to create a positive reciprocal feedback loop. On the whole, the present study demonstrates that HEY1 expression in HNSCC is regulated via the promotion of SOX2 and promotes EMT. The NOTCH4/HEY1 pathway is specifically upregulated via a positive reciprocal feedback loop mediated by the HEY1‑medaited regulation of NOTCH4 transcription, and SOX2 correlates with HEY1 expression in SCC from other primary sites.
- Subjects :
- Animals
Basic Helix-Loop-Helix Transcription Factors metabolism
Cell Cycle Proteins metabolism
Cell Line, Tumor
Cell Transformation, Neoplastic genetics
Datasets as Topic
Feedback, Physiological
Gene Expression Regulation, Neoplastic
Humans
Mice
Receptor, Notch4 metabolism
Signal Transduction genetics
Spheroids, Cellular
Squamous Cell Carcinoma of Head and Neck pathology
Up-Regulation
Xenograft Model Antitumor Assays
Basic Helix-Loop-Helix Transcription Factors genetics
Cell Cycle Proteins genetics
Epithelial-Mesenchymal Transition genetics
Receptor, Notch4 genetics
SOXB1 Transcription Factors metabolism
Squamous Cell Carcinoma of Head and Neck genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1791-2423
- Volume :
- 58
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- International journal of oncology
- Publication Type :
- Academic Journal
- Accession number :
- 33491747
- Full Text :
- https://doi.org/10.3892/ijo.2020.5156