Disruptor of telomeric silencing 1-like promotes ovarian cancer tumor growth by stimulating pro-tumorigenic metabolic pathways and blocking apoptosis.

Ovarian cancer is the leading cause of gynecological malignancy-related deaths. Current therapies for ovarian cancer do not provide meaningful and sustainable clinical benefits, highlighting the need for new therapies. We show that the histone H3K79 methyltransferase disruptor of telomeric silencing 1-like (DOT1L) is overexpressed in ovarian cancer and that a higher level of DOT1L expression correlates with shorter progression-free and overall survival (OS). Pharmacological inhibition of DOT1L (EPZ-5676, EPZ004777, and SGC0946) or genetic inhibition of DOT1L attenuates the growth of ovarian cancer cells in cell culture and in a mouse xenograft model of ovarian cancer. Transcriptome-wide mRNA expression profiling shows that DOT1L inhibition results in the downregulation of genes involved in cellular biosynthesis pathways and the upregulation of proapoptotic genes. Consistent with the results of transcriptome analysis, the unbiased large-scale metabolomic analysis showed reduced levels of several metabolites of the amino acid and nucleotide biosynthesis pathways after DOT1L inhibition. DOT1L inhibition also resulted in the upregulation of the NKG2D ligand ULBP1 and subsequent increase in natural killer (NK) cell-mediated ovarian cancer eradication. Collectively, our results demonstrate that DOT1L promotes ovarian cancer tumor growth by regulating apoptotic and metabolic pathways as well as NK cell-mediated eradication of ovarian cancer and identifies DOT1L as a new pharmacological target for ovarian cancer therapy.

卵巢癌是妇科恶性肿瘤相关死亡的首要原因。目前针对卵巢癌的治疗方法并未提供有意义且可持续的临床益处，这凸显了对新疗法的需求。我们发现组蛋白H3K79甲基转移酶端粒沉默破坏因子1样蛋白（DOT1L）在卵巢癌中过度表达，且DOT1L较高水平的表达与更短的无进展生存期和总生存期相关。DOT1L的药物抑制（EPZ - 5676、EPZ004777和SGC0946）或基因抑制可减弱卵巢癌细胞在细胞培养以及卵巢癌小鼠异种移植模型中的生长。全转录组mRNA表达谱分析表明，DOT1L抑制导致参与细胞生物合成途径的基因下调以及促凋亡基因上调。与转录组分析结果一致，无偏向的大规模代谢组学分析显示，DOT1L抑制后氨基酸和核苷酸生物合成途径的几种代谢物水平降低。DOT1L抑制还导致NKG2D配体ULBP1上调，以及自然杀伤（NK）细胞介导的卵巢癌清除作用随后增强。总之，我们的研究结果表明，DOT1L通过调节凋亡和代谢途径以及NK细胞介导的卵巢癌清除来促进卵巢癌肿瘤生长，并确定DOT1L是卵巢癌治疗的一个新的药理学靶点。