Higher LSD1 in Non-Seminomatous Germ Cell Tumors and LSD1 Inhibition by NCL1 Suppresses Embryonal Carcinoma Growth.

Lysine-specific demethylase 1 (LSD1/KDM1A) is a potential therapeutic target in non-seminomatous testicular germ cell tumors (NSGCTs). We assessed LSD1 and Ki-67 immunostaining in 74 histologically distinct tumor components from 53 patients with testicular germ cell tumors and studied the selective LSD1 inhibitor NCL1 in embryonal carcinoma models. LSD1 positivity was higher in pooled non-seminomatous than seminomatous components (p = 0.0104). Following Bonferroni correction, teratoma and yolk sac tumor components showed higher LSD1 positivity than seminoma, whereas the embryonal carcinoma-seminoma comparison did not reach statistical significance (adjusted p = 0.08). LSD1 positivity correlated with Ki-67 positivity. In embryonal carcinoma cells, NCL1 increased H3K9me2 enrichment at SOX2 and OCT4 promoter regions, decreased pluripotency-associated proteins and survivin, and increased cleaved caspase-3 and apoptotic cell populations while reducing cell viability. NCL1 also reduced viability in cisplatin-adapted cells and further reduced viability when combined with cisplatin in parental cells. In vivo, treatment initiated before tumors became measurable suppressed subsequent xenograft outgrowth, whereas treatment of established xenografts did not significantly inhibit growth at the doses tested. Together, the histological findings and responses observed in embryonal carcinoma models support LSD1 as a potential therapeutic target for further investigation in NSGCT; NCL1 efficacy in other histological subtypes and against established tumors remains to be established.