Xu Xin, Nagel Stefan, Quentmeier Hilmar, Wang Zhanju, Pommerenke Claudia, Dirks Wilhelm G, Macleod Roderick A F, Drexler Hans G, Hu Zhenbo
a Laboratory for Stem Cell and Regenerative Medicine , The Affiliated Hospital of Weifang Medical University , Weifang , Shandong , China.
b Department of Human and Animal Cell Culture , Leibniz-Institute DSMZ-German Collection of Microorganisms and Cell Cultures , Braunschweig , Germany.
Leuk Lymphoma. 2018 Jan;59(1):204-213. doi: 10.1080/10428194.2017.1324156. Epub 2017 May 25.
KDM3B reportedly shows both tumor-suppressive and tumor-promoting activities in leukemia. The function of KDM3B is likely cell-type dependent and its seeming functional discordance may reflect its phenotypic dependence on downstream targets. Here, we first showed the underexpression of KDM3B in acute myeloid leukemia (AML) patients and AML cell lines with MLL-AF6/9 or PML-RARA translocations. Overexpression of KDM3B repressed colony formation of AML cell line with 5q deletion. We then performed global microarray profiling to identify potential downstream targets of KDM3B, notably HOXA1, which was verified by real time PCR and Western blotting. We further showed KDM3B binding at retinoic acid response elements (RARE) but not at the promoter region of HOXA1 gene. KDM3B knockdown resulted in increased mono-methylation but decreased di-methylation of H3K9 at RARE while eschewing the promoter region of HOXA1. Collectively, we found that KDM3B exhibits potential tumor-suppressive activity and transcriptionally modulates HOXA1 expression via RARE in AML.
据报道，KDM3B在白血病中既表现出肿瘤抑制活性，也表现出肿瘤促进活性。KDM3B的功能可能依赖于细胞类型，其看似不一致的功能可能反映了其对下游靶点的表型依赖性。在这里，我们首先发现KDM3B在伴有MLL-AF6/9或PML-RARA易位的急性髓系白血病（AML）患者和AML细胞系中表达不足。KDM3B的过表达抑制了5q缺失的AML细胞系的集落形成。然后，我们进行了全基因组微阵列分析，以确定KDM3B的潜在下游靶点，特别是HOXA1，这通过实时PCR和蛋白质印迹法得到了验证。我们进一步发现KDM3B结合在视黄酸反应元件（RARE）上，但不结合在HOXA1基因的启动子区域。KDM3B敲低导致RARE处H3K9的单甲基化增加，但二甲基化减少，同时避开HOXA1的启动子区域。总的来说，我们发现KDM3B在AML中表现出潜在的肿瘤抑制活性，并通过RARE转录调节HOXA1的表达。
