Evaluation of lysine specific demethylase 1 as a potential novel target of oral cancer therapy

Abstract

INTRODUCTION: Lysine-specific demethylase 1 (LSD1) plays a crucial role in controlling cell homeostasis in health and disease. LSD1 is elevated in oral cancer and promotes metastasis and correlates with poor prognosis. The objective of this study is to determine the mechanism by which LSD1 plays a critical role in suppressing oral squamous cell carcinoma (OSCC) development. METHODS: The effect of knocking down LSD1 and the use of LSD1 inhibitor (SP2509) was investigated using 4-NQO mouse models in vivo. The mice were sacrificed, and their tongues were subjected to real-time PCR analysis, hematoxylin and eosin staining, pathological analysis and immunohistochemistry staining for different markers. The effect of SP2509 and different inhibitors on human squamous cell carcinoma (HSC3) was investigated. Cell proliferation assays were used to evaluate the effect of SP2509 alone and in combination with other inhibitors on HSC3 cells. RESULTS: The data showed that LSD1 knockout mice showed inhibition of tongue OSCC, downregulation of oncogenic genes. Immunostaining analysis confirmed the downregulation of PD-L1, YAP and other oncogenic factors in LSD1 knockout mice. CONCLUSION: Genetic deletion of LSD1 in Keratin14-Cre-Lsd1floxed mice provided a novel model to study epigenetic attenuation of HNSCC and provided a proof-of-concept that Lsd1 could be a specific target during tongue OSCC. Next, the pharmacological attenuation of Lsd1 with specific small molecule LSD1 inhibitor, SP,2509, inhibited pathological changes and provided evidence that SP2509 could be used for translational studies. Next, SP2509 was shown to be useful for immunotherapy and combination therapy applications. Overall, this study identified that LSD1 is a key regulator of OSCC. In addition, targeting LSD1 with SP2509 has an implication for immunotherapy, combination therapy, and future translational studies.