Epigenetic Silencing of 15-Hydroxyprostaglandin Dehydrogenase by Histone Methyltransferase EHMT2/G9a in Cholangiocarcinoma.
Epigenetic Silencing of 15-Hydroxyprostaglandin Dehydrogenase by Histone Methyltransferase EHMT2/G9a in Cholangiocarcinoma.
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DOI：
10.1158/1541-7786.mcr-21-0536
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发表时间：
2022-03-01
期刊：
影响因子：
--
通讯作者：
Wu T
中科院分区：
文献类型：
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作者：
Zhang J;Chen W;Ma W;Song K;Lee S;Han C;Wu T
胆管癌（CCA）是一种致命的恶性肿瘤，治疗选择很少。 NAD+ 依赖性 15-羟基前列腺素脱氢酶 (15-PGDH) 已被证明可以在体外和异种移植模型中抑制 CCA 细胞生长。然而，15-PGDH 在 CCA 发展中的作用尚未得到研究，15-PGDH 基因调控机制仍不清楚。在这里，我们通过使用小鼠模型评估了 15-PGDH 在 CCA 发育中的作用，该模型采用水动力尾静脉注射表达 Notch1 胞内结构域和 myr-Akt 的基于转座酶的质粒，同时注射或不注射 15-PGDH 表达质粒。我们的结果表明，15-PGDH 过度表达可有效阻止 CCA 的发展。通过患者数据挖掘和实验方法，我们提供了新的证据，证明 15-PGDH 被组蛋白甲基转移酶 G9a 表观遗传沉默。我们观察到 15-PGDH 和 G9a 表达在人类和小鼠 CCA 中呈负相关。通过使用 CCA 细胞和小鼠模型，我们表明 G9a 抑制可恢复 15-PGDH 表达并在体外和体内抑制 CCA。从机制上讲，我们的数据表明 G9a 通过与 E-box 结合 Myc/Max 异二聚体的蛋白质-蛋白质相互作用被招募到 15-PGDH 基因启动子。然后，招募的 G9a 通过增强 H3K9 的甲基化来沉默 15-PGDH 基因。我们进一步的实验已确定 STAT4 是参与 G9a 调节 15-PGDH 的关键转录因子。总的来说，我们的研究结果揭示了一种新的 G9a-15PGDH 信号轴，它与 CCA 的发生和进展密切相关。
Cholangiocarcinoma (CCA) is a lethal malignancy with few therapeutic options. NAD+-dependent 15-hydroxyprostaglandin dehydrogenase (15-PGDH) has been shown to inhibit CCA cell growth in vitro and in xenograft models. However, the role of 15-PGDH in CCA development has not been investigated and the mechanism for 15-PGDH gene regulation remains unclear. Here, we evaluated the role of 15-PGDH in CCA development by using a mouse model with hydrodynamic tail vein injection of transposase-based plasmids expressing Notch1 intracellular domain and myr-Akt, with or without co-injection of 15-PGDH expression plasmids. Our results reveal that 15-PGDH overexpression effectively prevents CCA development. Through patient data mining and experimental approaches, we provide novel evidences that 15-PGDH is epigenetically silenced by histone methyltransferase G9a. We observe that 15-PGDH and G9a expressions are inversely correlated in both human and mouse CCAs. By using CCA cells and mouse models, we show that G9a inhibition restores 15-PGDH expression and inhibited CCA in vitro and in vivo. Mechanistically, our data indicate that G9a is recruited to 15-PGDH gene promoter via protein-protein interaction with the E-box binding Myc/Max heterodimer. The recruited G9a then silences 15-PGDH gene through enhanced methylation of H3K9. Our further experiments have led to the identification of STAT4 as a key transcription factor involved in the regulation of 15-PGDH by G9a. Collectively, our findings disclose a novel G9a-15PGDH signaling axis which is importantly implicated in CCA development and progression.