Department of Otolaryngology, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan 44033, Korea.
Department of Radiation Oncology, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan 44033, Korea.
Biomolecules. 2021 Apr 18;11(4):599. doi: 10.3390/biom11040599.
EPHA3, a member of the EPH family, is overexpressed in various cancers. We demonstrated previously that EPHA3 is associated with radiation resistance in head and neck cancer via the PTEN/Akt/EMT pathway; the inhibition of EPHA3 significantly enhances the efficacy of radiotherapy in vitro and in vivo. In this study, we investigated the mechanisms of PTEN regulation through EPHA3-related signaling. Increased DNA methyltransferase 1 (DNMT1) and enhancer of zeste homolog 2 (EZH2) levels, along with increased histone H3 lysine 27 trimethylation (H3K27me3) levels, correlated with decreased levels of PTEN in radioresistant head and neck cancer cells. Furthermore, PTEN is regulated in two ways: DNMT1-mediated DNA methylation, and EZH2-mediated histone methylation through EPHA3/C-myc signaling. Our results suggest that EPHA3 could display a novel regulatory mechanism for the epigenetic regulation of PTEN in radioresistant head and neck cancer cells.
EPH 家族的成员 EPHA3 在各种癌症中过表达。我们之前证明，通过 PTEN/Akt/EMT 通路，EPHA3 与头颈部癌症的辐射抗性有关；抑制 EPHA3 可显著提高体外和体内放射治疗的疗效。在这项研究中，我们通过与 EPHA3 相关的信号通路研究了 PTEN 调节的机制。在耐辐射的头颈部癌细胞中，与 PTEN 水平降低相关的是 DNA 甲基转移酶 1（DNMT1）和 EZH2 水平的增加，以及组蛋白 H3 赖氨酸 27 三甲基化（H3K27me3）水平的增加。此外，PTEN 通过两种方式进行调节：通过 EPHA3/C-myc 信号传导的 DNMT1 介导的 DNA 甲基化和 EZH2 介导的组蛋白甲基化。我们的结果表明，EPHA3 可能对头颈部癌细胞中 PTEN 的表观遗传调控表现出一种新的调节机制。
