BACKGROUND: Bromodomain and extra-terminal domain (BET) proteins are important epigenetic regulators that facilitate the transcription of genes in chromatin areas linked to acetylated histones. JQ1, a BET inhibitor (BETi), has anti-proliferative and apoptosis activity against many cancers including oral squamous cell carcinoma (OSCC). In this research, we investigated the mechanism underlying the effects of JQ1 in OSCC and investigated strategies to increase its therapeutic potential. METHODS: The OSCC Cal27 and SCC25 cell lines were used for in vitro experiments. Cells were treated with JQ1 and/or siRNA targeting PD-L1 (siPD-L1), and cell viability, apoptosis, and cell cycle were evaluated by cell proliferation assay, colony formation assay, apoptosis, and cell cycle analysis. Levels of cleaved caspase-3, p53, BRD4, PD-L1, and FOXM1 were determined by quantitative real-time PCR and Western blot. The effects of single inhibitor or combination inhibitor treatment on tumors derived from Cal27 cells in mice were monitored. RESULTS: FOXM1 and PD-L1 were downregulated by JQ-1 in a dose-dependent manner. Combined JQ1 and siPD-L1 treatment synergistically inhibited cell growth and induced apoptosis and cell cycle arrest in vitro and synergistically inhibited tumor growth in vivo compared with single treatments. The combination treatment also synergistically suppressed FOXM1 and PD-L1 signaling pathways in OSCC cells. CONCLUSION: Our research suggests that FOXM1 and PD-L1 are targets of BETi in OSCC cells and indicate that combining PD-L1 blockade with BETi may be a useful therapeutic approach in OSCC through further suppressing FOXM1 and PD-L1.
BACKGROUND: Bromodomain and extra-terminal domain (BET) proteins are important epigenetic regulators that facilitate the transcription of genes in chromatin areas linked to acetylated histones. JQ1, a BET inhibitor (BETi), has anti-proliferative and apoptosis activity against many cancers including oral squamous cell carcinoma (OSCC). In this research, we investigated the mechanism underlying the effects of JQ1 in OSCC and investigated strategies to increase its therapeutic potential. METHODS: The OSCC Cal27 and SCC25 cell lines were used for in vitro experiments. Cells were treated with JQ1 and/or siRNA targeting PD-L1 (siPD-L1), and cell viability, apoptosis, and cell cycle were evaluated by cell proliferation assay, colony formation assay, apoptosis, and cell cycle analysis. Levels of cleaved caspase-3, p53, BRD4, PD-L1, and FOXM1 were determined by quantitative real-time PCR and Western blot. The effects of single inhibitor or combination inhibitor treatment on tumors derived from Cal27 cells in mice were monitored. RESULTS:FOXM1 and PD-L1 were downregulated by JQ-1 in a dose-dependent manner. Combined JQ1 and siPD-L1 treatment synergistically inhibited cell growth and induced apoptosis and cell cycle arrest in vitro and synergistically inhibited tumor growth in vivo compared with single treatments. The combination treatment also synergistically suppressed FOXM1 and PD-L1 signaling pathways in OSCC cells. CONCLUSION: Our research suggests that FOXM1 and PD-L1 are targets of BETi in OSCC cells and indicate that combining PD-L1 blockade with BETi may be a useful therapeutic approach in OSCC through further suppressing FOXM1 and PD-L1.