A novel PAD4/SOX4/PU.1 signaling pathway is involved in the committed differentiation of acute promyelocytic leukemia cells into granulocytic cells.
A novel PAD4/SOX4/PU.1 signaling pathway is involved in the committed differentiation of acute promyelocytic leukemia cells into granulocytic cells.
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一种新的 PAD4/SOX4/PU.1 信号通路参与急性早幼粒细胞白血病细胞向粒细胞的定向分化。
DOI：
10.18632/oncotarget.6551
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发表时间：
2016-01-19
期刊：
影响因子：
--
通讯作者：
Jiang G
中科院分区：
文献类型：
--
作者：
Song G;Shi L;Guo Y;Yu L;Wang L;Zhang X;Li L;Han Y;Ren X;Guo Q;Bi K;Jiang G
全反式视黄酸 (ATRA) 治疗通过蛋白酶体降解 PML-RARα 融合蛋白（通常会促进急性早幼粒细胞白血病 (APL)），治愈率 > 80%。然而，最近的证据表明，ATRA 还可以促进 PML-RARα 阴性的白血病细胞的分化，例如 HL-60 细胞。在这里，HL-60 细胞的基因表达谱用于研究 APL 分化受损的替代机制。编码 PAD4 的肽基精氨酸脱亚胺酶 4 (PADI4) 的表达在 ATRA 诱导的分化过程中得到恢复，PAD4 是一种翻译后将精氨酸转化为瓜氨酸的蛋白质。我们进一步发现 PADI4 启动子的高甲基化与其在 HL-60 和 NB4（PML-RARα 阳性）细胞中的转录抑制有关。从功能上讲，PAD4 在 ATRA 暴露后易位到细胞核中，并促进 ATRA 介导的分化。使用 RNAi 敲低或电穿孔介导的 PADI4 传递以及染色质免疫沉淀的机制研究有助于确定 PU.1 为 PAD4 调节的间接靶标，SOX4 为直接靶标。事实上，PAD4 以 SOX4 依赖性方式调节 SOX4 介导的 PU.1 表达，从而调节分化过程。总而言之，我们的结果强调了 PAD4 与 APL 中 DNA 高甲基化之间的关联，并证明靶向 PAD4 或调节其下游效应器可能是临床控制分化的一种有前景的策略。
All-trans retinoic acid (ATRA) treatment yields cure rates > 80% through proteasomal degradation of the PML-RARα fusion protein that typically promotes acute promyelocytic leukemia (APL). However, recent evidence indicates that ATRA can also promote differentiation of leukemia cells that are PML-RARα negative, such as HL-60 cells. Here, gene expression profiling of HL-60 cells was used to investigate the alternative mechanism of impaired differentiation in APL. The expression of peptidylarginine deiminase 4 (PADI4), encoding PAD4, a protein that post-translationally converts arginine into citrulline, was restored during ATRA-induced differentiation. We further identified that hypermethylation in the PADI4 promoter was associated with its transcriptional repression in HL-60 and NB4 (PML-RARα positive) cells. Functionally, PAD4 translocated into the nucleus upon ATRA exposure and promoted ATRA-mediated differentiation. Mechanistic studies using RNAi knockdown or electroporation-mediated delivery of PADI4, along with chromatin immunoprecipitation, helped identify PU.1 as an indirect target and SOX4 as a direct target of PAD4 regulation. Indeed, PAD4 regulates SOX4-mediated PU.1 expression, and thereby the differentiation process, in a SOX4-dependent manner. Taken together, our results highlight an association between PAD4 and DNA hypermethylation in APL and demonstrate that targeting PAD4 or regulating its downstream effectors may be a promising strategy to control differentiation in the clinic.