Combined inhibition of EZH2 and the autotaxin-LPA-LPA2 axis exerts synergistic antitumor effects on colon cancer cells
Combined inhibition of EZH2 and the autotaxin-LPA-LPA2 axis exerts synergistic antitumor effects on colon cancer cells
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DOI：
10.1016/j.canlet.2023.216226
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发表时间：
2023-06-02
期刊：
影响因子：
9.7
通讯作者：
Zhang，Junjie
中科院分区：
文献类型：
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作者：
Long，Yang;Wang，Yuqin;Zhang，Junjie
自分泌运动因子 (ATX)，也称为 ENPP2，是溶血磷脂酸 (LPA) 生产的关键酶。 LPA作用于细胞膜上的受体，促进细胞增殖和迁移，因此ATX-LPA轴在肿瘤发生中起着至关重要的作用。临床数据分析表明，在结肠癌中，ATX与多梳抑制复合物2（PRC2）的酶催化亚基EZH2的表达存在很强的负相关性。在这里，我们证明 ATX 表达被 PRC2 表观遗传沉默，PRC2 被 MTF2 招募并催化 ATX 启动子区域的 H3K27me3 修饰。 EZH2 抑制是一种有前景的癌症治疗策略，EZH2 抑制剂可诱导结肠癌细胞中 ATX 的表达。以EZH2和ATX为靶点，它们的联合抑制对结肠癌细胞发挥协同抗肿瘤作用。此外，LPA受体2（LPA2）缺陷显着增强结肠癌细胞对EZH2抑制剂的敏感性。总之，我们的研究将 ATX 确定为一种新的 PRC2 靶基因，并发现共靶向 EZH2 和 ATX-LPA-LPA2 轴可能是结肠癌的潜在联合治疗策略。
Autotaxin (ATX), also known as ENPP2, is the key enzyme in lysophosphatidic acid (LPA) production. LPA acts on its receptors on the cell membrane to promote cell proliferation and migration, and thus, the ATX-LPA axis plays a critical role in tumorigenesis. Clinical data analysis indicated that in colon cancer, there is a strong negative correlation between the expression of ATX and EZH2, the enzymatic catalytic subunit of polycomb repressive complex 2 (PRC2). Here, we demonstrated that ATX expression was epigenetically silenced by PRC2, which was recruited by MTF2 and catalyzed H3K27me3 modification in the ATX promoter region. EZH2 inhibition is a promising strategy for cancer treatment, and ATX expression is induced in colon cancer cells by EZH2 inhibitors. With both EZH2 and ATX as targets, their combined inhibition exerted synergistic antitumor effects on colon cancer cells. In addition, LPA receptor 2 (LPA2) deficiency significantly enhanced the sensitivity to EZH2 inhibitors in colon cancer cells. In summary, our study identified ATX as a novel PRC2 target gene and found that cotargeting EZH2 and the ATX-LPA-LPA2 axis may be a potential combination therapy strategy for colon cancer.