Guangdong Province Key Laboratory of Pharmaceutical Functional Genes, MOE Key Laboratory of Gene Function and Regulation, School of Life Sciences, and The Fifth Affiliated Hospital, Sun Yat-sen University, Guangzhou 510275, China; Guangdong Provincial Key Laboratory of Biomedical Imaging, Guangdong Provincial Engineering Research Center of Molecular Imaging, and The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai 519000, China.
Guangdong Province Key Laboratory of Pharmaceutical Functional Genes, MOE Key Laboratory of Gene Function and Regulation, School of Life Sciences, and The Fifth Affiliated Hospital, Sun Yat-sen University, Guangzhou 510275, China.
Mol Ther. 2023 Jan 4;31(1):105-118. doi: 10.1016/j.ymthe.2022.09.019. Epub 2022 Sep 30.
Epigenetic reprogramming is a promising therapeutic strategy for aggressive cancers, but its limitations in vivo remain unclear. Here, we showed, in detailed studies of data regarding 410 patients with human hepatocellular carcinoma (HCC), that increased histone methyltransferase DOT1L triggered epithelial-mesenchymal transition-mediated metastasis and served as a therapeutic target for human HCC. Unexpectedly, although targeting DOT1L in vitro abrogated the invasive potential of hepatoma cells, abrogation of DOT1L signals hardly affected the metastasis of hepatoma in vivo. Macrophages, which constitute the major cellular component of the stroma, abrogated the anti-metastatic effect of DOT1L targeting. Mechanistically, NF-κB signal elicited by macrophage inflammatory response operated via a non-epigenetic machinery to eliminate the therapeutic efficacy of DOT1L targeting. Importantly, therapeutic strategy combining DOT1L-targeted therapy with macrophage depletion or NF-κB inhibition in vivo effectively and successfully elicited cancer regression. Moreover, we found that the densities of macrophages in HCC determined malignant cell DOT1L-associated clinical outcome of the patients. Our results provide insight into the crosstalk between epigenetic reprogramming and cancer microenvironments and suggest that strategies to influence the functional activities of inflammatory cells may benefit epigenetic reprogramming therapy.
表观遗传重编程是一种有前途的侵袭性癌症治疗策略，但在体内的局限性尚不清楚。在这里，我们通过对 410 名肝细胞癌 (HCC) 患者的数据进行详细研究表明，组蛋白甲基转移酶 DOT1L 的增加引发了上皮-间充质转化介导的转移，并可作为人类 HCC 的治疗靶点。出乎意料的是，尽管在体外靶向 DOT1L 消除了肝癌细胞的侵袭潜力，但阻断 DOT1L 信号对体内肝癌的转移影响甚微。构成基质主要细胞成分的巨噬细胞消除了 DOT1L 靶向的抗转移作用。从机制上讲，巨噬细胞炎症反应引发的 NF-κB 信号通过非表观遗传机制消除了 DOT1L 靶向的治疗效果。重要的是，体内联合 DOT1L 靶向治疗与巨噬细胞耗竭或 NF-κB 抑制的治疗策略可有效成功地引发癌症消退。此外，我们发现 HCC 中巨噬细胞的密度决定了恶性细胞 DOT1L 相关的患者临床结局。我们的研究结果深入了解了表观遗传重编程与癌症微环境之间的相互作用，并表明影响炎症细胞功能活动的策略可能有益于表观遗传重编程治疗。
