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EZH2-mediated upregulation of ROS1 oncogene promotes oral cancer metastasis

C-H Shih1, Y-J Chang1, W-C Huang2

  • 1Institute of Molecular Medicine, National Tsing Hua University, Hsinchu, Taiwan, ROC.

Oncogene
|August 1, 2017
PubMed

Insights

Researchers identified ROS1 (an oncogene) as a key driver of oral squamous cell carcinoma (OSCC) metastasis. Targeting ROS1, alongside EGFR, may offer a new effective therapy for oral cancer patients.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Genetics

Background:

  • Current anti-epidermal growth factor receptor (EGFR) therapies for oral cancer show limited efficacy due to resistance.
  • There is a need for alternative therapeutic targets to improve oral cancer treatment outcomes.

Purpose of the Study:

  • To identify novel oncogenes driving oral squamous cell carcinoma (OSCC) metastasis.
  • To investigate the role of ROS1 in OSCC progression and metastasis.
  • To explore ROS1 as a potential therapeutic target for oral cancer.

Main Methods:

  • Analysis of ROS1 expression in 188 oral cancer patient tumors.
  • Mechanistic studies involving gene expression, histone modification (EZH2, H3K27 trimethylation), and transcription factors (STAT1).
  • In vitro and in vivo experiments using OSCC cell lines and xenograft models (tail-vein injection, oral cavity).

Main Results:

  • Upregulated ROS1 expression strongly correlated with lung and lymph node metastasis in OSCC patients.
  • ROS1 activation in OSCC results from gene overexpression, not gene rearrangement.
  • Reduced EZH2 levels lead to decreased H3K27 trimethylation, promoting ROS1 target gene (CXCL1, GLI1) expression via STAT1.
  • Down-regulating ROS1 inhibited OSCC cell proliferation and lung metastasis in preclinical models.

Conclusions:

  • ROS1 is a significant driver of OSCC metastasis and a potential therapeutic target.
  • The mechanism involves EZH2-mediated epigenetic regulation of ROS1 expression.
  • Co-targeting ROS1 and EGFR presents a promising strategy for oral cancer therapy.

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