Twist1 is essential in maintaining mesenchymal state and tumor-initiating properties in synovial sarcoma

Keun Woo Lee, Nam Kyung Lee, Seokjin Ham, Tae Young Roh, Seok Hyung Kim

Research output: Contribution to journalArticlepeer-review

33 Scopus citations

Abstract

Synovial sarcoma is an aggressive mesenchymal tumor with dual differentiation; epithelial and mesenchymal differentiation. However, the molecular mechanisms behind tumorigenesis and dual differentiation have remained elusive. In this study, we investigated whether Twist1 is an essential transcription factor for maintaining tumor-initiating cell properties in synovial sarcoma. First, we identified that Twist1 is overexpressed in most cases of synovial sarcoma (SS) samples as well as in two synovial sarcoma cell lines (HSSYII, SW982). Additionally, Twist1 depletion led to down-regulation of mesenchymal markers and up-regulation of epithelial markers in SS cell lines. The migratory and invasive abilities of SS cell lines were also significantly reduced following the loss of Twist1. These results indicate that Twist1 plays an essential role in the maintenance of mesenchymal character in SS. Furthermore, knock-down of Twist1 induced G1 cycle arrest and apoptosis as well as remarkable reduction in the sphere-forming cell subpopulation and side population cells. Moreover, Twist1 knock-down profoundly inhibited the growth of synovial sarcoma xenograft in nude mice compared to controls indicating that Twist1 is essential for tumor initiating cell properties. To explore transcriptional regulation by Twist1 at the genomic level, Chromatin immunoprecipiation-solexa whole genome sequencing (ChIP-SEQ) and cDNA microarray analysis were performed. Mesenchymal differentiation/proliferation and PDGF related genes were found to be affected by Twist1. Finally, depletion of SS18-SSX fusion oncoprotein by RNA inference induced down-regulation of Twist1, implying that Twist1 is regulated by SS18-SSX. Hence, our results suggest that Twist1 is an essential transcription factor for the maintenance of mesenchymal characters and tumor initiating properties of synovial sarcoma.

Original languageEnglish
Pages (from-to)62-73
Number of pages12
JournalCancer Letters
Volume343
Issue number1
DOIs
StatePublished - 1 Feb 2014

Bibliographical note

Funding Information:
This work was also supported by National Research Foundation (2010-0020259), Republic of Korea.

Funding Information:
This study was supported by a grant of the Korean Health Technology R&D Project, Ministry of Health & Welfare, Republic of Korea. (A111809).

Keywords

  • Apoptosis
  • EMT
  • Synovial sarcoma
  • Tumor-initiating cells
  • Twist1

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