Disordered choline metabolism is associated with tumor progression. Glycerophosphocholine phosphodiesterase 1 (GPCPD1) is critical for cleaving glycerophosphocholine (GPC) to produce choline. However, whether and how GPCPD1 is epigenetically regulated remains largely unknown. In the current study, we report that histone H3 lysine 9 (H3K9) methyltransferase GLP (G9a-like Protein) is essential for transcriptional activation of GPCPD1 through H3K9me1 to promote tumor cell migration and invasion. Knocking down GLP or inhibiting its methyltransferase activity impaired GPCPD1 expression and decreased the choline levels. Importantly, we confirmed that both GPCPD1 and choline levels are positively correlated with cancer cell migration. The reduced migration and invasion of GPCPD1-knockdown cells were rescued by choline treatment. Interestingly, GPCPD1 gene expression was found regulated by transcription factor Krüppel-like Factor 5 (KLF5). KLF5 recruitment was GLP-dependent and was indispensable for GPC-induced GPCPD1 expression. These data suggest that GLP promotes tumor cell migration and invasion by transcriptionally activating GPCPD1. GLP and KLF5 are potential therapeutic targets in future cancer treatment.

胆碱代谢紊乱与肿瘤进展相关。甘油磷酸胆碱磷酸二酯酶 1 (GPCPD1) 对于裂解甘油磷酸胆碱 (GPC) 产生胆碱至关重要。然而，GPCPD1 是否以及如何受到表观遗传调控仍然很大程度上未知。在目前的研究中，我们报道组蛋白H3赖氨酸9（H3K9）甲基转移酶GLP（G9a样蛋白）对于通过H3K9me1转录激活GPCPD1以促进肿瘤细胞迁移和侵袭至关重要。敲低 GLP 或抑制其甲基转移酶活性会损害 GPCPD1 表达并降低胆碱水平。重要的是，我们证实 GPCPD1 和胆碱水平与癌细胞迁移呈正相关。 GPCPD1 敲低细胞的迁移和侵袭减少可以通过胆碱处理来恢复。有趣的是，GPCPD1基因表达被发现受到转录因子 Krüppel 样因子 5 (KLF5) 的调节。 KLF5 的招募是 GLP 依赖性的，对于 GPC 诱导的 GPCPD1 表达是不可或缺的。这些数据表明GLP通过转录激活GPCPD1来促进肿瘤细胞迁移和侵袭。 GLP和KLF5是未来癌症治疗的潜在治疗靶点。