Abstract:
Chronic Lymphocytic Leukemia (CLL) patients have a defective expression of the proapoptotic protein p66Shc and of its transcriptional factor STAT4, which evoke molecular abnormalities, impairing apoptosis and worsening disease prognosis and severity. p66Shc expression is epigenetically controlled and transcriptionally modulated by STAT4; epigenetic modifiers are deregulated in CLL cells and specific histone deacetylases (HDACs) like HDAC1, are overexpressed. Reactivation of STAT4/p66Shc expression may represent an attractive and challenging strategy to reverse CLL apoptosis defects. New selective class I HDAC inhibitors (HDACis, 6a-g) were developed with increased potency over existing agents and preferentially interfering with the CLL-relevant isoform HDAC1, to unveil the role of class I HDACs in the upregulation of STAT4 expression, which upregulates p66Shc expression and hence normalizes CLL cell apoptosis. 6c (chlopynostat) was identified as a potent HDAC1i with a superior profile over entinostat. 6c induces marked apoptosis of CLL cells compared with SAHA, which was associated with an upregulation of STAT4/p66Shc protein expression. The role of HDAC1, but not HDAC3, in the epigenetic upregulation of STAT4/p66Shc was demonstrated for the first time in CLL cells and was validated in siRNA-induced HDAC1/HDAC3 knock-down EBV-B cells. To sum up, HDAC1 inhibition is necessary to reactivate STAT4/p66Shc expression in patients with CLL. 6c is one of the most potent HDAC1is known to date and represents a novel pharmacological tool for reversing the impairment of the STAT4/p66Shc apoptotic machinery.
摘要:
慢性淋巴细胞白血病(CLL)患者的促凋亡蛋白p66Shc及其转录因子STAT4表达缺陷,引起分子异常,细胞凋亡受损,疾病预后和严重程度恶化。p66Shc表达受STAT4的表观遗传控制和转录调节;表观遗传修饰剂在CLL细胞中失调,并且特异性组蛋白脱乙酰酶(HDACs)如HDAC1被过表达。STAT4/p66Shc表达的再激活可能代表了逆转CLL凋亡缺陷的有吸引力和挑战性的策略。新的选择性I类HDAC抑制剂(HDACis,6a-g)比现有药物具有更高的效力,并优先干扰CLL相关的同工型HDAC1,以揭示I类HDACs在STAT4表达上调中的作用,上调p66Shc表达,从而使CLL细胞凋亡正常化。6c(氯吡诺坦)被鉴定为有效的HDAC1i,其特征优于恩替诺坦。与SAHA相比,6c诱导CLL细胞显著凋亡,这与STAT4/p66Shc蛋白表达上调有关。HDAC1而不是HDAC3在STAT4/p66Shc的表观遗传上调中的作用首次在CLL细胞中得到证实,并在siRNA诱导的HDAC1/HDAC3敲低EBV-B细胞中得到验证。总而言之,HDAC1抑制是CLL患者重新激活STAT4/p66Shc表达所必需的。6c是迄今为止已知的最有效的HDAC1之一,代表了一种新的逆转STAT4/p66Shc凋亡机制损伤的药理学工具。