Targeting inflammatory macrophages rebuilds therapeutic efficacy of DOT1L inhibition in hepatocellular carcinoma
Targeting inflammatory macrophages rebuilds therapeutic efficacy of DOT1L inhibition in hepatocellular carcinoma
复制标题
DOI：
10.1016/j.ymthe.2022.09.019
复制
发表时间：
2023-01-04
影响因子：
12.4
通讯作者：
Wei，Yuan
中科院分区：
文献类型：
--
作者：
Yang，Yi-Bin;Wu，Cai-Yuan;Wei，Yuan
表观遗传重编程是治疗侵袭性癌症的一种很有前景的治疗策略，但其在体内的局限性尚不清楚。在此，我们通过对410例人肝细胞癌（HCC）患者的详细研究表明，组蛋白甲基转移酶DOT1L升高可触发上皮-间质过渡介导的转移，并可作为人肝细胞癌的治疗靶点。出乎意料的是，虽然体外靶向DOT1Lin消除了肝癌细胞的侵袭潜能，但消除DOT1L信号几乎不影响肝组织体内的转移。巨噬细胞是构成基质的主要细胞成分，它取消了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，将dot1l靶向治疗与巨噬细胞清除或NF-κB抑制相结合的治疗策略有效且成功地诱导了癌症的消退。此外，我们发现HCC中巨噬细胞的密度决定了患者恶性细胞dot1l相关的临床预后。我们的研究结果揭示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利于表观遗传重编程治疗。
Epigenetic reprogramming is a promising therapeutic strategy for aggressive cancers, but its limitationsin vivoremain 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 DOT1Lin vitroabrogated the invasive potential of hepatoma cells, abrogation of DOT1L signals hardly affected the metastasis of hepatomain 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 inhibitionin vivoeffectively 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.