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.
Highlights
Histone demethylases play critical roles in oncogenesis [1, 2]
Immunohistochemistry for Lysine-specific demethylase 1 (LSD1) performed on human clinical specimens representing normal adjacent, dysplastic, hyperplastic and oral squamous cell carcinoma (OSCC) tissues revealed that LSD1 expression is elevated in tumor tissues (Figure 1A)
We evaluated whether LSD1 expression increases during OSCC progression by using a tissue microarray containing a diverse population of 80 tumors of the larynx, tongue and submandibular gland as well as facial and other oral tumor types (Figure 1B)
Summary
Lysine-specific demethylase 1 (LSD1) is a nuclear histone demethylase and a member of the flavin adenine dinucleotide (FAD)-dependent amine oxidase (AO) family that functions as an epigenetic regulator. AOs include diverse regulatory enzymes such as lysine-specific demethylases as well as the extracellular matrix lysyl oxidase enzyme family, serum amine oxidases, monoamine oxidases, and vascular adhesion protein-1 [3]. LSD1 can demethylate H3K4 during gene repression and H3K9 during gene activation, indicating a dual and context-dependent role in transcriptional regulation. LSD1 is inappropriately upregulated in lung, liver, brain and esophageal cancers through diverse regulatory mechanisms, including transcriptional activation and protein stabilization [7,8,9,10,11]. Inactivation of LSD1 promotes G1 arrest and induces differentiationspecific genes by selectively modulating methylation of H3K4 and H3K9 [12]
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