Department of Pathology, West China Hospital of Sichuan University, Chengdu, China.
Department of Medical Oncology, The Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China.
Genes Genomics. 2024 Feb;46(2):203-212. doi: 10.1007/s13258-023-01434-1. Epub 2023 Jul 31.
Epigenetic alteration plays an essential role in the occurrence and development of extranodal natural killer/T cell lymphoma (ENKTL). Histone methyltransferase (HMT) KMT2D is an epigenetic regulator that plays different roles in different tumors, but its role and mechanism in ENKTL are still unclear.
We performed immunohistochemical staining of 112 ENKTL formalin-fixed paraffin-embedded (FFPE) samples. Then, we constructed KMT2D knockdown cell lines and conducted research on cell biological behavior. Finally, to further investigate KMT2D-mediated downstream genes, ChIP-seq and ChIP -qPCR was performed.
The low expression of KMT2D was related to a decreased abundance in histone H3 lysine 4 mono- and trimethylation (H3K4me1/3). In KMT2D knockdown YT and NK-YS cells, cell proliferation was faster (P < 0.05), apoptosis was decreased (P < 0.05), the abundance of S phase cells was increased (P < 0.05), and the level of H3K4me1 was decreased. Notably, ChIP-seq revealed two crucial genes and pathways downregulated by KMT2D.
KMT2D is a tumor suppressor gene that mediates H3K4me1 and influences ENKTL proliferation and apoptosis by regulating the cell cycle. Moreover, in ENKTL, serum- and glucocorticoid-inducible kinase-1 (SGK1) and suppressor of cytokine signaling-1 (SOCS1) are downstream genes of KMT2D.
表观遗传改变在结外自然杀伤/T 细胞淋巴瘤（ENKTL）的发生和发展中起着至关重要的作用。组蛋白甲基转移酶（HMT）KMT2D 是一种表观遗传调节剂，在不同的肿瘤中发挥不同的作用，但它在 ENKTL 中的作用和机制尚不清楚。
我们对 112 例 ENKTL 福尔马林固定石蜡包埋（FFPE）样本进行了免疫组织化学染色。然后，我们构建了 KMT2D 敲低细胞系，并进行了细胞生物学行为研究。最后，为了进一步研究 KMT2D 介导的下游基因，我们进行了 ChIP-seq 和 ChIP-qPCR。
KMT2D 的低表达与组蛋白 H3 赖氨酸 4 单甲基化和三甲基化（H3K4me1/3）的丰度降低有关。在 KMT2D 敲低的 YT 和 NK-YS 细胞中，细胞增殖更快（P<0.05），细胞凋亡减少（P<0.05），S 期细胞的丰度增加（P<0.05），H3K4me1 的水平降低。值得注意的是，ChIP-seq 揭示了两个关键基因和由 KMT2D 下调的途径。
KMT2D 是一种肿瘤抑制基因，通过调节细胞周期介导 H3K4me1，并影响 ENKTL 的增殖和凋亡。此外，在 ENKTL 中，血清和糖皮质激素诱导激酶-1（SGK1）和细胞因子信号转导抑制物-1（SOCS1）是 KMT2D 的下游基因。
