The antioxidant protein peroxiredoxin 4 is epigenetically down regulated in acute promyelocytic leukemia.
The antioxidant protein peroxiredoxin 4 is epigenetically down regulated in acute promyelocytic leukemia.
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DOI：
10.1371/journal.pone.0016340
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发表时间：
2011-01-20
期刊：
影响因子：
3.7
通讯作者：
Touw IP
中科院分区：
文献类型：
--
作者：
Palande KK;Beekman R;van der Meeren LE;Beverloo HB;Valk PJ;Touw IP
抗氧化剂过氧化物氧还蛋白（PRDX）蛋白家族由6个成员组成，涉及多种细胞反应，包括生长因子信号转导。PRDX 4存在于内质网（ER）中，在那里它通过降低H2 O2水平来局部控制氧化应激。我们最近提供的证据表明，PRDX 4的调节功能，从骨髓生长因子受体，粒细胞集落刺激因子受体（G-CSFR）的信号转导。在激活后，配体诱导的G-CSFR经历内吞作用并经由早期内体路由，在早期内体中其与ER驻留的PRDX 4物理相互作用。PRDX 4负调节G-CSFR介导的信号传导。在这里，我们研究了PRDX 4是否在急性髓细胞白血病（AML）中受到影响;研究了PRDX 4的基因组改变和表达水平。我们发现，涉及PRDX 4的基因组异常在AML中是罕见的。然而，我们发现与正常早幼粒细胞和不同分子亚型的AML相比，急性早幼粒细胞白血病（APL）中PRDX 4表达水平显著降低。随后，研究了DNA甲基化和组蛋白修饰在APLs中PRDX 4沉默中的可能作用。我们表明，减少的表达不是由于甲基化的CpG岛在PRDX 4的启动子区域，但与组蛋白3赖氨酸残基27（H3 K27 me 3）和赖氨酸残基4（H3 K4 me 3）在PRDX 4的转录起始位点（TSS）的三甲基化的增加，指示二价组蛋白编码参与转录沉默。这些发现表明，抗氧化蛋白PRDX 4对G-CSF反应的控制可能在APL中受到干扰。
The antioxidant peroxiredoxin (PRDX) protein family comprises 6 members, which are implicated in a variety of cellular responses, including growth factor signal transduction. PRDX4 resides in the endoplasmic reticulum (ER), where it locally controls oxidative stress by reducing H2O2 levels. We recently provided evidence for a regulatory function of PRDX4 in signal transduction from a myeloid growth factor receptor, the granulocyte colony-stimulating factor receptor (G-CSFR). Upon activation, the ligand-induced G-CSFR undergoes endocytosis and routes via the early endosomes where it physically interacts with ER-resident PRDX4. PRDX4 negatively regulates G-CSFR mediated signaling. Here, we investigated whether PRDX4 is affected in acute myeloid leukemia (AML); genomic alterations and expression levels of PRDX4 were investigated. We show that genomic abnormalities involving PRDX4 are rare in AML. However, we find a strong reduction in PRDX4 expression levels in acute promyelocytic leukemia (APL) compared to normal promyelocytes and different molecular subtypes of AML. Subsequently, the possible role of DNA methylation and histone modifications in silencing of PRDX4 in APLs was investigated. We show that the reduced expression is not due to methylation of the CpG island in the promoter region of PRDX4 but correlates with increased trimethylation of histone 3 lysine residue 27 (H3K27me3) and lysine residue 4 (H3K4me3) at the transcriptional start site (TSS) of PRDX4, indicative of a bivalent histone code involved in transcriptional silencing. These findings suggest that the control of G-CSF responses by the antioxidant protein PRDX4 may be perturbed in APL.
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