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Cancer Lett. 2016 Apr 28;374(1):12-21. doi: 10.1016/j.canlet.2016.02.004. Epub 2016 Feb 9.

The histone demethylase LSD1 is a novel oncogene and therapeutic target in oral cancer.

Author information

1
Jiangsu Key Laboratory of Oral Disease, Nanjing Medical University, Jiangsu 210029, China.
2
Jiangsu Key Laboratory of Oral Disease, Nanjing Medical University, Jiangsu 210029, China; Department of Oral and Maxillofacial Surgery, Nanjing Medical University, Jiangsu 210029, China.
3
Department of Oral and Maxillofacial Surgery, Nanjing Medical University, Jiangsu 210029, China.
4
Department of Oral Pathology, Nanjing Medical University, Jiangsu 210029, China.
5
Jiangsu Key Laboratory of Oral Disease, Nanjing Medical University, Jiangsu 210029, China; Department of Oral Pathology, Nanjing Medical University, Jiangsu 210029, China.
6
Jiangsu Key Laboratory of Oral Disease, Nanjing Medical University, Jiangsu 210029, China. Electronic address: omfs_njmu@163.com.

Abstract

The histone demethylase LSD1 functions as a key pro-oncogene and attractive therapeutic target in human cancer. Here we sought to interrogate the oncogenic roles of LSD1 in OSCC tumorigenesis and therapeutic intervention by integrating chemical-induced OSCC model, genetic and pharmacological loss-of-function approaches. Our data revealed that aberrant LSD1 overexpression in OSCC was significantly associated with tumor aggressiveness and shorter overall survival. Increased abundance of LSD1 was detected along with disease progression in DMBA- or 4NQO-induced OSCC animal models. LSD1 depletion via siRNA-mediated knockdown in OSCC cells resulted in impaired cell proliferation, migration/invasion, tumorsphere formation and reduced xenograft growth while inducing cell apoptosis and enhancing chemosensitivity to 5-FU. Moreover, treatments of LSD1 chemical inhibitors (pargyline and tranylcypromine) induced its protein reduction probably via enhanced protein degradation and produced similar phenotypic changes resembling LSD1 silencing in OSCC cells. Pharmacological inhibition of LSD1 by intraperitoneal delivery of these inhibitors resulted in impaired xenograft overgrowth. Taken together, our data reveal the tumorigenic roles of LSD1 and identified LSD1 as a novel biomarker with diagnostic and prognostic significance, and also establish that targeting LSD1 by chemical inhibitors is a viable therapeutic strategy against OSCC.

KEYWORDS:

Epigenetic modification; Histone demethylase; LSD1; Oral cancer

PMID:
26872725
DOI:
10.1016/j.canlet.2016.02.004
[Indexed for MEDLINE]

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