EZH2-mediated upregulation of ROS1 oncogene promotes oral cancer metastasis

C. H. Shih, Y. J. Chang, W. C. Huang, T. H. Jang, H. J. Kung, W. C. Wang, M. H. Yang, M. C. Lin, S. F. Huang, S. W. Chou, E. Chang, H. Chiu, T. Y. Shieh, Y. J. Chen, L. H. Wang, L. Chen

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

Current anti-epidermal growth factor receptor (EGFR) therapy for oral cancer does not provide satisfactory efficacy due to drug resistance or reduced EGFR level. As an alternative candidate target for therapy, here we identified an oncogene, ROS1, as an important driver for oral squamous cell carcinoma (OSCC) metastasis. Among tumors from 188 oral cancer patients, upregulated ROS1 expression strongly correlated with metastasis to lung and lymph nodes. Mechanistic studies uncover that the activated ROS1 results from highly expressed ROS1 gene instead of gene rearrangement, a phenomenon distinct from other cancers. Our data further reveal a novel mechanism that reduced histone methyltransferase EZH2 leads to a lower trimethylation of histone H3 lysine 27 suppressive modification, relaxes chromatin, and promotes the accessibility of the transcription factor STAT1 to the enhancer and the intron regions of ROS1 target genes, CXCL1 and GLI1, for upregulating their expressions. Down-regulation of ROS1 in highly invasive OSCC cells, nevertheless, reduces cell proliferation and inhibits metastasis to lung in the tail-vein injection and the oral cavity xenograft models. Our findings highlight ROS1 as a candidate biomarker and therapeutic target for OSCC. Finally, we demonstrate that co-targeting of ROS1 and EGFR could potentially offer an effective oral cancer therapy.

Original languageEnglish
Pages (from-to)6542-6554
Number of pages13
JournalOncogene
Volume36
Issue number47
DOIs
Publication statusPublished - Nov 23 2017
Externally publishedYes

Fingerprint

Mouth Neoplasms
Oncogenes
Up-Regulation
Epidermal Growth Factor Receptor
Neoplasm Metastasis
Squamous Cell Carcinoma
STAT1 Transcription Factor
Lung
Gene Rearrangement
Therapeutics
Drug Resistance
Heterografts
Histones
Introns
Genes
Lysine
Chromatin
Mouth
Veins
Neoplasms

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

Cite this

Shih, C. H., Chang, Y. J., Huang, W. C., Jang, T. H., Kung, H. J., Wang, W. C., ... Chen, L. (2017). EZH2-mediated upregulation of ROS1 oncogene promotes oral cancer metastasis. Oncogene, 36(47), 6542-6554. https://doi.org/10.1038/onc.2017.262

EZH2-mediated upregulation of ROS1 oncogene promotes oral cancer metastasis. / Shih, C. H.; Chang, Y. J.; Huang, W. C.; Jang, T. H.; Kung, H. J.; Wang, W. C.; Yang, M. H.; Lin, M. C.; Huang, S. F.; Chou, S. W.; Chang, E.; Chiu, H.; Shieh, T. Y.; Chen, Y. J.; Wang, L. H.; Chen, L.

In: Oncogene, Vol. 36, No. 47, 23.11.2017, p. 6542-6554.

Research output: Contribution to journalArticle

Shih, CH, Chang, YJ, Huang, WC, Jang, TH, Kung, HJ, Wang, WC, Yang, MH, Lin, MC, Huang, SF, Chou, SW, Chang, E, Chiu, H, Shieh, TY, Chen, YJ, Wang, LH & Chen, L 2017, 'EZH2-mediated upregulation of ROS1 oncogene promotes oral cancer metastasis', Oncogene, vol. 36, no. 47, pp. 6542-6554. https://doi.org/10.1038/onc.2017.262
Shih CH, Chang YJ, Huang WC, Jang TH, Kung HJ, Wang WC et al. EZH2-mediated upregulation of ROS1 oncogene promotes oral cancer metastasis. Oncogene. 2017 Nov 23;36(47):6542-6554. https://doi.org/10.1038/onc.2017.262
Shih, C. H. ; Chang, Y. J. ; Huang, W. C. ; Jang, T. H. ; Kung, H. J. ; Wang, W. C. ; Yang, M. H. ; Lin, M. C. ; Huang, S. F. ; Chou, S. W. ; Chang, E. ; Chiu, H. ; Shieh, T. Y. ; Chen, Y. J. ; Wang, L. H. ; Chen, L. / EZH2-mediated upregulation of ROS1 oncogene promotes oral cancer metastasis. In: Oncogene. 2017 ; Vol. 36, No. 47. pp. 6542-6554.
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