β-arrestin1 通过调控 BCR/ABL H4 乙酰化促进慢性髓系白血病的进展。
β-Arrestin1 promotes the progression of chronic myeloid leukaemia by regulating BCR/ABL H4 acetylation.
机构信息
1] Center for Clinical Molecular Medicine, Children's Hospital, Chongqing Medical University, Chongqing 400014, China [2] Department of Laboratory Medicine, Children's Hospital, Chongqing Medical University, Chongqing 400014, China [3] Ministry of Education Key Laboratory of Child Development and Disorders, Children's Hospital, Chongqing Medical University, Chongqing 400014, China [4] Key Laboratory of Pediatrics in Chongqing, Children's Hospital, Chongqing Medical University, Chongqing 400014, China.
Chongqing Stem Cell Therapy Engineering Technique Center, Children's Hospital, Chongqing Medical University, Chongqing 400014, China.
出版信息
Br J Cancer. 2014 Jul 29;111(3):568-76. doi: 10.1038/bjc.2014.335. Epub 2014 Jun 17.
BACKGROUND
β-Arrestins are scaffold proteins that interact with various cellular signals. Although β-arrestin2 mediates the initiation and progression of myeloid leukaemia, the critical role of β-arrestin1 in the chronic myeloid leukaemia (CML) is still unknown. The aim of this study is to investigate the essential function of β-arrestin1 in CML.
METHODS
The expressions of β-arrestin1 and BCR/ABL in CML patients, animal models and K562 cells were measured by RT-PCR, immunofluorescence and western blotting. The effect of β-arrestin1 on CML animal models and K562 cells by colony formation, MTT and survival analysis were assessed. BCR/ABL H4 acetylation was analysed through the use of Chromatin-immunoprecipitation (ChIP) -on-chip and confirmed by ChIP respectively. Co-immunoprecipitation and confocal were examined for the binding of β-arrestin1 with enhancer of zeste homologue 2 (EZH2).
RESULTS
The higher expression of β-arrestin1 is positively correlated with clinical phases of CML patients. Depletion of β-arrestin1 decelerates progression of K562 and primary cells, and increases survival of CML mice. Importantly, silenced β-arrestin1 results in the decrease of BCR/ABL H4 acetylation level in K562 cells. Further data illustrate that nuclear β-arrestin1 binds to EZH2 to mediate BCR/ABL acetylation and thus regulates cell progression in K562 cells and the survival of CML mice.
CONCLUSIONS
Our findings reveal a novel function of β-arrestin1 binding to EZH2 to promote CML progression by regulating BCR/ABL H4 acetylation.
背景
β-arrestin 是一种与各种细胞信号相互作用的支架蛋白。虽然 β-arrestin2 介导髓性白血病的起始和进展，但β-arrestin1 在慢性髓性白血病（CML）中的关键作用尚不清楚。本研究旨在探讨β-arrestin1 在 CML 中的重要功能。
方法
通过 RT-PCR、免疫荧光和 Western blot 检测 CML 患者、动物模型和 K562 细胞中β-arrestin1 和 BCR/ABL 的表达。通过集落形成、MTT 和生存分析评估β-arrestin1 对 CML 动物模型和 K562 细胞的影响。通过染色质免疫沉淀（ChIP）-on-chip 分析和 ChIP 分别分析 BCR/ABL H4 乙酰化。共免疫沉淀和共聚焦检测β-arrestin1 与增强子的结合EZH2 同源物 2（EZH2）。
结果
β-arrestin1 的高表达与 CML 患者的临床分期呈正相关。β-arrestin1 的耗竭会减缓 K562 和原代细胞的进展，并增加 CML 小鼠的存活率。重要的是，沉默β-arrestin1 会导致 K562 细胞中 BCR/ABL H4 乙酰化水平降低。进一步的数据表明，核β-arrestin1 与 EZH2 结合，介导 BCR/ABL 乙酰化，从而调节 K562 细胞的细胞进展和 CML 小鼠的存活。
结论
我们的研究结果揭示了β-arrestin1 与 EZH2 结合的新功能，通过调节 BCR/ABL H4 乙酰化来促进 CML 的进展。
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