Hypermethylation of PRDM1/Blimp-1 promoter in extranodal NK/T-cell lymphoma, nasal type: an evidence of predominant role in its downregulation
Hypermethylation of PRDM1/Blimp-1 promoter in extranodal NK/T-cell lymphoma, nasal type: an evidence of predominant role in its downregulation
复制标题
鼻型结外 NK/T 细胞淋巴瘤中 PRDM1/Blimp-1 启动子的高甲基化：其下调中起主导作用的证据
DOI：
10.1002/hon.2362
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发表时间：
2017-12-01
影响因子：
3.3
通讯作者：
Li, Ting
中科院分区：
文献类型：
--
作者：
Zhang, Zhang;Liang, Li;Li, Ting
PRDM 1表达缺失在鼻型结源性NK/T细胞淋巴瘤（EN-NK/T-NT）中很常见，但启动子甲基化在沉默PRDM 1表达中的作用仍不清楚。因此，我们进行焦磷酸测序分析，以评估在体内和体外的PRDM 1基因的启动子甲基化，分析甲基化和其表达之间的关联，并评估PRDM 1重新表达的细胞效应。25例EN-NK/T-NT患者中11例（44.0%）及NK 92、NKL细胞中PRDM 1基因启动子区甲基化。PRDM 1启动子甲基化与PRDM 1在体内和体外的表达显著相关，与EN-NK/T-NT中miR-223的基因缺失和异常表达相比，PRDM 1的启动子甲基化主要导致PRDM 1表达的丧失。PRDM 1表达显著恢复去甲基化处理，诱导细胞增殖抑制，细胞周期阻滞，凋亡增加。我们还发现PRDM 1的再表达可下调Ets-1、T-bet、颗粒酶B和c-myc的表达。我们的研究结果表明，PRDM 1基因启动子甲基化在EN-NK/T-NT中PRDM 1表达下调中起主导作用，显著影响肿瘤细胞的生物学行为。
The loss of PRDM1 expression is common in extranodal NK/T-cell lymphoma, nasal type (EN-NK/T-NT), but the role of promoter methylation in silencing PRDM1 expression remains unclear. Hence, we performed pyrosequencing analysis to evaluate the promoter methylation of PRDM1 gene in vivo and in vitro, to analyze the association between methylation and its expression, and to assess cellular effects of PRDM1 reexpression. The promoter hypermethylation of PRDM1 gene was detected in 11 of 25 EN-NK/T-NT cases (44.0%) and NK92 and NKL cells. The promoter hypermethylation of PRDM1 was significantly correlated with PRDM1 expression in vivo and in vitro, predominantly contributing to the loss of PRDM1 expression compared with genetic deletion and aberrant expression of miR-223 in EN-NK/T-NT. PRDM1 expression was significantly restored by demethylation treatment, which induced cell proliferation suppression, cell cycle arrest, and apoptosis increase. We also found that PRDM1 reexpression could downregulate the expression of Ets-1, T-bet, granzyme B, and c-myc. Our findings demonstrated that the promoter hypermethylation of PRDM1 harbored a predominant role in the downregulation of PRDM1 expression, significantly affecting the biological behavior of tumor cells in EN-NK/T-NT.