Twist1 induces endothelial differentiation of tumour cells through the Jagged1-KLF4 axis

Hsiao-Fan Chen; Chi-Hung Huang; Chung-Ji Liu; Jung-Jyh Hung; Chih-Chin Hsu; Shu-Chun Teng; Kou-Juey Wu

doi:10.1038/ncomms5697

Twist1 induces endothelial differentiation of tumour cells through the Jagged1-KLF4 axis

Nat Commun. 2014 Aug 22:5:4697. doi: 10.1038/ncomms5697.

Authors

Hsiao-Fan Chen¹, Chi-Hung Huang², Chung-Ji Liu³, Jung-Jyh Hung⁴, Chih-Chin Hsu⁵, Shu-Chun Teng⁶, Kou-Juey Wu⁷

Affiliations

¹ Institute of Biochemistry and Molecular Biology, National Yang-Ming University, Taipei 112, Taiwan.
² Taiwan Advance Biopharm (TABP), Inc., Xizhi City, New Taipei City 221, Taiwan.
³ Department of Dentistry, Taipei Mackay Memorial Hospital, Taipei 104, Taiwan.
⁴ 1] Institute of Biochemistry and Molecular Biology, National Yang-Ming University, Taipei 112, Taiwan [2] Department of Surgery, Taipei Veterans General Hospital, Taipei 112, Taiwan.
⁵ Department of Physical Medicine and Rehabilitation, ChangGung Memorial Hospital, Keelung 204, Taiwan.
⁶ Graduate Institute of Microbiology, College of Medicine, National Taiwan University, Taipei 100, Taiwan.
⁷ 1] Institute of Biochemistry and Molecular Biology, National Yang-Ming University, Taipei 112, Taiwan [2] Genome Research Center, National Yang-Ming University, Taipei 112, Taiwan [3] Research Center for Tumor Medical Science, China Medical University, Taichung 40402, Taiwan.

PMID: 25146389
DOI: 10.1038/ncomms5697

Abstract

The mechanisms controlling tumour-induced angiogenesis are presently not clear. In principle, angiogenesis can be achieved through the activation of endothelial cells in existing vessels or by transdifferentiation of tumour cells into endothelial cells. However, whether tumour cells can go through a prior epithelial-mesenchymal transition and further differentiate into endothelial cells remains unknown. Here we show that overexpression of Twist1, a transcriptional regulator that induces and promotes cancer metastasis, leads to endothelial differentiation in head and neck cancer (HNC) cells. Induction of Jagged1 expression by Twist1 is essential for Twist1-induced endothelial differentiation. The Jagged1/Notch signalling subsequently activates KLF4, inducing stem-like properties in HNC cells and conferring them with drug resistance. Our results indicate that the Twist1-Jagged1/KLF4 axis is essential both for transdifferentiation of tumour cells into endothelial cells and for chemoresistance acquisition.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Calcium-Binding Proteins / genetics
Calcium-Binding Proteins / metabolism*
Cell Differentiation
Cell Line, Tumor / pathology
Cell Movement
Cell Transdifferentiation
Drug Resistance, Neoplasm
Endothelial Cells / metabolism
Endothelial Cells / pathology*
Female
Humans
Intercellular Signaling Peptides and Proteins / genetics
Intercellular Signaling Peptides and Proteins / metabolism*
Jagged-1 Protein
Kruppel-Like Factor 4
Kruppel-Like Transcription Factors / genetics
Kruppel-Like Transcription Factors / metabolism*
Membrane Proteins / genetics
Membrane Proteins / metabolism*
Mice, Inbred BALB C
Molecular Sequence Data
Neoplasms, Experimental / drug therapy
Neoplasms, Experimental / genetics
Neoplasms, Experimental / pathology
Nuclear Proteins / genetics
Nuclear Proteins / metabolism*
Serrate-Jagged Proteins
Signal Transduction
Twist-Related Protein 1 / genetics
Twist-Related Protein 1 / metabolism*
Xenograft Model Antitumor Assays

Substances

Calcium-Binding Proteins
Intercellular Signaling Peptides and Proteins
JAG1 protein, human
Jag1 protein, mouse
Jagged-1 Protein
KLF4 protein, human
Klf4 protein, mouse
Kruppel-Like Factor 4
Kruppel-Like Transcription Factors
Membrane Proteins
Nuclear Proteins
Serrate-Jagged Proteins
TWIST1 protein, human
Twist-Related Protein 1

Associated data

GENBANK/GSE57756