LSD1 is a Potential Biomarker and Therapeutic Target of OSCC

Objectives: Lysine-specific demethylase 1 (LSD1) is a nuclear histone demethylase, a member of the flavin adenine dinucleotide (FAD)-dependent amine oxidase (AO) family that function as an epigenetic regulator. The goal of the study is to evaluate if LSD1 can be used as a potential biomarker and therapeutic target of OSCC.
Methods: The approval to obtain human tissues was obtained from Institutional Review Board, and animal experiments were approved by Institutional Animal Care and Use Committee, Boston University. LSD1 immunostaining was performed in clinical oral SCC and malignant oral cancer tissue microarray sections with the anti-LSD1 antibody. LSD1 loss- and gain- of-function were studied in orthotropic OSCC mouse models. Pharmacological inhibition of LSD1 was studied by using LSD1 inhibitor (GSK-LSD1) on cell proliferation, mRNA expression, and pre-existing patient-derived xenograft models.
Results: LSD1 expression is increased in clinical oral squamous cell carcinoma (OSCC), malignant oral cancers and in The Cancer Genome Atlas (TCGA) Head and Neck Squamous Cell Carcinoma dataset with progressive grade and stage. LSD1 knockdown in metastatic HSC-3 oral cancer cells inhibited OSCC growth and metastasis in orthotopic oral cancer mouse models, whereas overexpression of LSD1 promoted OSCC growth and metastasis suggesting that LSD1 is a key regulator of OSCC. Pharmacological inhibition of LSD1 using a small molecule specific inhibitor of LSD1, GSK-LSD1, affected a number of oncogenic factors in patient-derived tonsillar SCC, myoepithelial and osteosarcoma cells. In addition, gene set enrichment analysis also showed that GSK-LSD1 increases p53 expression, increases apoptosis while inhibiting c-myc and beta-catenin-induced oncogenic transcriptional networks. GSK-LSD1 inhibited proliferation of patient-derived oral cancer cells and pre-existing patent-derived tonsil SCC tumor xenografts in nude mice.
Conclusions: LSD1 expression could be a potential biomarker for malignant OSCC. We for the first time provide evidence that GSK-LSD1 inhibits clinical OSCC patient-derived cell proliferation, oncogenic transcriptional network, and growth in PDX models. This study has a strong translational potential for personalized clinical OSCC therapies.