Knockdown of XAB2 enhances all-trans retinoic acid-induced cellular differentiation in all-trans retinoic acid-sensitive and -resistant cancer cells
Knockdown of XAB2 enhances all-trans retinoic acid-induced cellular differentiation in all-trans retinoic acid-sensitive and -resistant cancer cells
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DOI：
10.1158/0008-5472.can-06-1638
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发表时间：
2007-02-01
期刊：
影响因子：
11.2
通讯作者：
Mizutani, Shuki
中科院分区：
文献类型：
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作者：
Ohnuma-Ishikawa, Kumiko;Morio, Tomohiro;Mizutani, Shuki
着色性干皮病A组(XPA)结合蛋白2(XAB2)由855个氨基酸组成，含有15个四肽重复序列，与Cockayne综合征A、B组蛋白和RNA聚合酶II以及XPA相关。体外和体内研究表明，XAB2参与了前mRNA的剪接、转录和转录偶联的DNA修复，导致着床前死亡，对小鼠胚胎发育是必不可少的。维甲酸可有效治疗癌前疾病，包括色素性干皮病和其他皮肤病，如光老化。因此，我们专注于确定在全反式维甲酸处理的情况下XAB2对细胞分化的影响。在本研究中，我们发现XAB2的过表达抑制了全反式维甲酸诱导的人横纹肌肉瘤细胞系的细胞分化，而在生理(10(-9)-10(-8)摩尔/L)和治疗性(10(-7)摩尔/L)浓度的全反式维甲酸下，小干扰RNA(SiRNA)抑制了XAB2的表达，促进了人早幼粒白血病细胞系HL60对全反式维甲酸敏感的细胞分化。此外，我们还发现XAB2与核内的维甲酸受体α(RARα)和组蛋白脱乙酰基酶3有关。最后，利用针对XAB2的siRNA，我们发现在治疗浓度(10(-6)mol/L)的ATRA诱导下，神经母细胞瘤耐药细胞系IMR-32发生了细胞分化。这些结果有力地表明，XAB2是RAR核心受体复合体的一个组成部分，对ATRA诱导的细胞分化具有抑制作用，XAB2作为肿瘤治疗的一个重要方面，在ATRA介导的细胞分化中发挥作用。
Xeroderma pigmentosum group A (XPA)-binding protein 2 (XAB2) is composed of 855 amino acids, contains 15 tetratricopeptide repeat motifs, and associates with Cockayne syndrome group A and B proteins and RNA polymerase II, as well as XPA. In vitro and in vivo studies showed that XAB2 is involved in pre-mRNA splicing, transcription, and transcription-coupled DNA repair, leading to preimplantation lethality, and is essential for mouse embryogenesis. Retinoids are effective for the treatment of preneoplastic diseases including xeroderma pigmentosum and other dermatologic diseases such as photoaging. We therefore focused on defining the effect of XAB2 on cellular differentiation in the presence of ATRA treatment. In the present study, we showed that overexpression of XAB2 inhibited ATRA-induced cellular differentiation in human rhabdomyosarcoma cell line, and that knockdown of XAB2 by small interfering RNA (siRNA) increased ATRA-sensitive cellular differentiation in the human promyelocytic leukemia cell line HL60 at both physiologic (10(-9)-10(-8) mol/L) and therapeutic (10(-7) mol/L) concentrations of ATRA. Moreover, we found that XAB2 was associated with retinoic acid receptor a (RAR alpha) and histone deacetylase 3 in the nuclei. Finally, using siRNA against XAB2, we showed that the ATRA-resistant neuroblastoma cell line IMR-32 underwent cellular differentiation induced by ATRA at a therapeutic concentration (10(-6) mol/L). These results strongly suggest that XAB2 is a component of the RAR coreprescor complex with an inhibitory effect on ATRA-induced cellular differentiation and that XAB2 plays a role in ATRA-mediated cellular differentiation as an important aspect of cancer therapy.