Therapeutically targeting head and neck squamous cell carcinoma through synergistic inhibition of LSD1 and JMJD3 by TCP and GSK-J1
Menée in vitro et sur des modèles animaux, cette étude met en évidence les effets synergiques de TCP et de GSK-J1, deux molécules inhibant respectivement les histones déméthylases LSD1 et JMJD3, contre les cellules d'un carcinome épidermoïde de la tête et du cou
Background : The histone demethylase LSD1 is a key mediator driving tumorigenesis, which holds potential as a promising therapeutic target. However, treatment with LSD1 inhibitors alone failed to result in complete cancer regression. Methods : The synergistic effects of TCP (a LSD1 inhibitor) and GSK-J1 (a JMJD3 inhibitor) against HNSCC were determined in vitro and in preclinical animal models. Genes modulated by chemical agents or siRNAs in HNSCC cells were identified by RNA-seq and further functionally interrogated by bioinformatics approach. Integrative siRNA-mediated gene knockdown, rescue experiment and ChIP-qPCR assays were utilised to characterise the mediators underlying the therapeutic effects conferred by TCP and GSK-J1. Results : Treatment with TCP and GSK-J1 impaired cell proliferation, induced apoptosis and senescence in vitro, which were largely recapitulated by simultaneous LSD1 and JMJD3 knockdown. Combinational treatment inhibited tumour growth and progression in vivo. Differentially expressed genes modulated by TCP and GSK-J1 were significantly enriched in cell proliferation, apoptosis and cancer-related pathways. SPP1 was identified as the mediator of synergy underlying the pro-apoptosis effects conferred by TCP and GSK-J1. Co-upregulation of LSD1 and JMJD3 associated with worse prognosis in patients with HNSCC. Conclusions : Our findings revealed a novel therapeutic strategy of simultaneous LSD1 and JMJD3 inhibition against HNSCC.