Oncotarget

Priority Research Papers:

Inhibition of LSD1 epigenetically attenuates oral cancer growth and metastasis

Saqer F. Alsaqer, Mustafa M. Tashkandi, Vinay K. Kartha, Ya-Ting Yang, Yazeed Alkheriji, Andrew Salama, Xaralabos Varelas, Maria Kukuruzinska, Stefano Monti and Manish V. Bais _

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Oncotarget. 2017; 8:73372-73386. https://doi.org/10.18632/oncotarget.19637

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Abstract

Saqer F. Alsaqer1,*, Mustafa M. Tashkandi1,*, Vinay K. Kartha2,3, Ya-Ting Yang1, Yazeed Alkheriji1, Andrew Salama4, Xaralabos Varelas5, Maria Kukuruzinska1, Stefano Monti2,3 and Manish V. Bais1

1 Department of Molecular and Cell Biology, Boston University Henry M. Goldman School of Dental Medicine, Boston, MA, USA

2 Bioinformatics Program, Boston University, Boston, MA, USA

3 Section of Computational Biomedicine, Boston University School of Medicine, Boston, MA, USA

4 Department of Oral and Maxillofacial Surgery, Boston University Henry M. Goldman School of Dental Medicine, Boston, MA, USA

5 Department of Biochemistry, Boston University School of Medicine, Boston, MA, USA

* These authors have contributed equally to this work

Correspondence to:

Manish V. Bais, email:

Keywords: LSD1, CTGF, OSCC, PDX, orthotopic mouse model

Received: December 28, 2016 Accepted: July 14, 2017 Published: July 27, 2017

Abstract

Lysine-specific demethylase 1 (LSD1) is a nuclear histone demethylase and a member of the amine oxidase (AO) family. LSD1 is a flavin-containing AO that specifically catalyzes the demethylation of mono- and di-methylated histone H3 lysine 4 through an FAD-dependent oxidative reaction. LSD1 is inappropriately upregulated in lung, liver, brain and esophageal cancers, where it promotes cancer initiation, progression, and metastasis. However, unlike other lysine-specific demethylases, the role and specific targets of LSD1 in oral squamous cell carcinoma (OSCC) pathogenesis remain unknown. We show that LSD1 protein expression was increased in malignant OSCC tissues in a clinical tissue microarray, and its expression correlated with progressive tumor stages. In an orthotopic oral cancer mouse model, LSD1 overexpression in aggressive HSC-3 cells promoted metastasis whereas knockdown of LSD1 inhibited tumor spread, suggesting that LSD1 is a key regulator of OSCC metastasis. Pharmacological inhibition of LSD1 using a specific small molecule inhibitor, GSK-LSD1, down-regulated EGF signaling pathway. Further, GSK-LSD1 attenuates CTGF/CCN2, MMP13, LOXL4 and vimentin expression but increased E-cadherin expression in pre-existing, patient-derived tonsillar OSCC xenografts. Similarly, GSK-LSD1 inhibited proliferation and CTGF expression in mesenchymal cells, including myoepithelial cells and osteosarcoma cells. In addition, gene set enrichment analysis revealed that GSK-LSD1 increased p53 expression and apoptosis while inhibiting c-myc, β-catenin and YAP-induced oncogenic transcriptional networks. These data reveal that aberrant LSD1 activation regulates key OSCC microenvironment and EMT promoting factors, including CTGF, LOXL4 and MMP13.


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