EZH2 Inhibitors Suppress Colorectal Cancer by Regulating Macrophage Polarization in the Tumor Microenvironment.
EZH2 Inhibitors Suppress Colorectal Cancer by Regulating Macrophage Polarization in the Tumor Microenvironment.
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DOI：
10.3389/fimmu.2022.857808
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发表时间：
2022
影响因子：
7.3
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EZH 2抑制剂（EZH 2 i）是一类靶向EZH 2发挥抗肿瘤功能的小分子抑制剂，刚刚获得美国食品和药物管理局（FDA）批准用于治疗患有局部晚期或转移性上皮样肉瘤的成人和青少年。EZH 2 i在几种实体瘤中的应用仍处于不同的临床试验阶段，需要进一步验证。作为一种关键的表观遗传调节因子，除了在控制肿瘤细胞增殖中的作用外，EZH 2还参与了包括巨噬细胞在内的各种免疫细胞的调节。但目前仍有争议的研究结果。结直肠癌（CRC）是一种常见的恶性肿瘤，其高度表达EZH 2，在全球范围内具有第三高发病率，并且是癌症相关死亡的第二大原因。研究表明，M2型肿瘤相关巨噬细胞（TAM）的数量与结直肠癌的进展和转移高度相关。在目前的研究中，我们的目的是研究EZH 2如何调节CRC肿瘤微环境（TME）中巨噬细胞的极化，并比较两种不同的EZH 2抑制剂EPZ 6438和GSK 126的作用。我们应用3D培养方法来证明EZH 2 i确实在体外抑制CRC细胞的增殖。在体内实验中，我们发现在EPZ 6438处理下，TME中的CD 206+巨噬细胞的百分比降低，但在GSK 126处理下，其增加。此外，在巨噬细胞和结直肠癌细胞的共培养体系中，EPZ 6438导致M1标志物的显著升高和M2标志物的显著降低。此外，通过ChIP-qPCR验证的机制研究表明，EZH 2 i抑制STAT 3启动子上EZH 2介导的H3 K27 me 3水平，STAT 3是M1巨噬细胞极化的必需转录因子。因此，我们的数据表明，EZH 2 i不仅直接抑制CRC细胞增殖，而且通过将M2偏斜成效应M1巨噬细胞来调节巨噬细胞以发挥肿瘤抑制作用。此外，我们的研究为更好地理解两种EZH 2 i的作用提供了新的见解：EPZ 6438和GSK 126，这可能为将来通过这种表观遗传方法靶向癌细胞和免疫细胞治疗CRC铺平道路。
EZH2 inhibitors (EZH2i), a class of small-molecule inhibitors that target EZH2 to exert anti-tumor functions, have just been approved by the US Food and Drug Administration (FDA) in treatment of adults and adolescents with locally advanced or metastatic epithelioid sarcoma. The application of EZH2i in several solid tumors is still in different stages of clinical trials and needs to be further validated. As a key epigenetic regulator, besides its role in controlling the proliferation of tumor cells, EZH2 has been implicated in the regulation of various immune cells including macrophages. But there are still controversial research results at present. Colorectal cancer (CRC) is a common malignant tumor that highly expresses EZH2, which has the third highest incidence and is the second leading cause of cancer-related death worldwide. Studies have shown that the numbers of M2-type tumor-associated macrophages (TAMs) are highly associated with the progression and metastasis of CRC. In the current study, we aim to investigate how EZH2 modulates the polarization of macrophages in the tumor microenvironment (TME) of CRC, and compare the role of two different EZH2 inhibitors, EPZ6438 and GSK126. We applied a 3D culture method to demonstrate that EZH2i did indeed suppress the proliferation of CRC cells in vitro. In vivo, we found that the percentage of CD206+ macrophages of the TME was decreased under the treatment of EPZ6438, but it increased upon GSK126 treatment. Besides, in the co-culture system of macrophages and CRC cells, EPZ6438 led to significant elevation of M1 markers and reduction of M2 markers. Furthermore, mechanistic studies validated by ChIP-qPCR demonstrated that EZH2i inhibit EZH2-mediated H3K27me3 levels on the promoters of STAT3, an essential transcription factor for M1 macrophage polarization. Therefore, our data suggested that EZH2i not only suppress CRC cell proliferation directly, but also regulate macrophage by skewing M2 into effector M1 macrophage to exert a tumor suppressive effect. Moreover, our study provided new insight for better understanding of the role of two kinds of EZH2i: EPZ6438 and GSK126, which may pave the way in treating CRC by targeting cancer cells and immune cells via this epigenetic approach in the future.