LSD1- induced signaling mechanisms inhibition sensitizes oral cancer for chemotherapy and immunotherapy
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Abstract
INTRODUCTION: Lysine-specific demethylase 1 (LSD1) is a nuclear histone demethylase. Our work shows that LSD1 expression progressively increases with tumor grade and stage in clinical oral squamous cell carcinoma (OSCC). The goal is to evaluate the LSD1 mechanism in OSCC by proteomics analysis and its application for immunotherapy and chemotherapy.METHODS: The animal experiments were approved by the Institutional Animal Care and Use Committee, Boston University. The conditional LSD1 knockout mice (K14Cre-Lsd1; Lsd1-/-) and littermates (Lsd1WT/WT) were treated with 4-Nitroquinoline 1-oxide (4NQO) followed by histology and proteomics analysis. Next, 4NQO-treated mice for 20 weeks were subjected to LSD1 inhibitor (SP2509) alone or in combination with Hippo signaling regulator YAP inhibitor (Verteporfin), anti-PD-1 or anti-PD-L1 antibodies for five weeks, followed by IHC and mRNA expression analysis.
RESULTS: Global unbiased proteomics analysis of 4NQO-induced OSCC from LSD1-/- compared to LSD1WT/WT (n=7/condition) showed inhibition of 40 differentially regulated proteins, reduction of canonical pathways signaling including EIF2, mTOR, VEGF, Integrin, ERK/MAPK, Glucocorticoid Receptor Signaling, Acute Phase Response and oxidative phosphorylation evaluated by IPA analysis. LSD1 inhibition attenuates EGF-, YAP-, and pro-inflammatory cytokine-induced pathways involved in oral cancer cell proliferation, migration, and oncogenic transformation. These pathways are validated in HSC-3 and CAL27, and LSD1 knockout OSCC mice. Next, studies in OSCC mice showed that the topical application of LSD1 inhibitor in combination with YAP inhibitor provides sensitivity to OSCC as compared to a single drug alone. LSD1 and YAP co-regulate each other. Finally, genetic, or pharmacological LSD1 inhibition showed to promote PD-L1 expression, thereby sensitizing to the combination of LSD1 inhibitor to anti-PD-1 therapy. Thus, LSD1 inhibition sensitizes to chemotherapy and immunotherapy combinations.
CONCLUSION: We showed for the first time that blocking LSD1 inhibits OSCC, a feed-forward loop oncogenic protein that exists in OSCC and promotes anti-tumor immunity. Next, the detailed mechanism of LSD1 in vitro and in vivo is being evaluated for application in chemotherapy and immunotherapy.
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2025