EZH2-mediated upregulation of ROS1 oncogene promotes oral cancer metastasis

Oncogene
C-H ShihL Chen

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...Continue Reading

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Citations

Aug 27, 2018·Journal of Cellular Biochemistry·Fatma SogutluCumhur Gunduz
Oct 2, 2018·International Journal of Oncology·Maria Fernanda Setúbal Destro RodriguesFabio Daumas Nunes
Mar 8, 2020·Clinical Epigenetics·Catarina SalgadoRemco van Doorn
Aug 8, 2020·Nature Reviews. Clinical Oncology·Alexander DrilonMonika A Davare
Jun 25, 2020·International Journal of Molecular Sciences·Yen-Chi TsaoLinyi Chen
Jul 31, 2020·Molecular Cancer Therapeutics·Mara GilardiFrancis Burrows

Related Concepts

ROS1 protein, human
GLI1 protein, human
CXCL1 protein, human
STAT1 protein, human
EZH2 protein, human
EGFR protein, human
Enhancer of Zeste Homolog 2 Protein
Zinc Finger Protein GLI1
Metazoa
Squamous Cell Carcinoma

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