Molecular sequelae of histone deacetylase inhibition in human malignant B cells
Molecular sequelae of histone deacetylase inhibition in human malignant B cells
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DOI：
10.1182/blood-2002-11-3514
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发表时间：
2003-05-15
期刊：
影响因子：
20.3
通讯作者：
Anderson, KC
中科院分区：
文献类型：
--
作者：
Mitsiades, N;Mitsiades, CS;Anderson, KC
组蛋白乙酰化调节基因表达、细胞分化和存活，并且由组蛋白乙酰转移酶（HAT）和组蛋白脱乙酰酶（HDAC）的相反活性调节。HDAC抑制导致乙酰化核小体组蛋白的积累，并诱导转化细胞的分化和/或凋亡。在这项研究中，我们表征了辛二酰苯胺异羟肟酸（SAHA），一系列基于异羟肟酸的HDAC抑制剂的原型，在B细胞恶性肿瘤（包括多发性骨髓瘤（MM）和相关疾病）的细胞系和患者细胞中的作用。SAHA在所有测试的肿瘤细胞中诱导凋亡，增加p21和p53蛋白水平和Rb的去磷酸化。我们还检测到Bid的裂解，表明Bcl-2家族成员在调节SAHA诱导的细胞死亡中的作用。Bcl-2 cDNA转染MMAS细胞完全废除SAHA诱导的凋亡，证实其保护作用。SAHA在MMAS细胞凋亡的早期阶段不诱导caspase-8、-9或-3的裂解，并且泛caspase抑制剂ZVAD-FMK不保护SAHA。相反，聚（ADP）核糖聚合酶（PARP）被切割的钙蛋白酶激活的模式指示，和钙蛋白酶抑制剂calpeptin废除SAHA诱导的细胞死亡。重要的是，SAHA致敏MMAS细胞死亡受体介导的凋亡，并抑制骨髓基质细胞（BMSCs）诱导的分泌白细胞介素6（IL-6）的MM细胞的结合，这表明它可以克服细胞粘附介导的耐药性。我们的研究描述了HDAC抑制剂介导抗MM活性和克服BM环境中耐药性的机制，并为SAHA的临床评价提供了框架，SAHA具有生物利用度，耐受性良好，口服后具有生物活性，可改善患者结局。(C)2003年，美国血液学会。
Histone acetylation modulates gene expression, cellular differentiation, and survival and is regulated by the opposing activities of histone acetyltransferases (HATs) and histone deacetylases (HDACs). HDAC inhibition results in accumulation of acetylated nucleosomal histones and induces differentiation and/or apoptosis in transformed cells. In this study, we characterized the effect of suberoylanilide hydroxamic acid (SAHA), the prototype of a series of hydroxamic acid-based HDAC inhibitors, in cell lines and patient cells from B-cell malignancies, including multiple myeloma (MM) and related disorders. SAHA induced apoptosis in all tumor cells tested, with increased p21 and p53 protein levels and dephosphorylation of Rb. We also detected cleavage of Bid, suggesting a role for Bcl-2 family members in regulation of SAHA-induced cell death. Transfection of Bcl-2 cDNA into MMAS cells completely abrogated SAHA-induced apoptosis, confirming its protective role. SAHA did not induce cleavage of caspase-8, -9, or -3 in MMAS cells during the early phase of apoptosis, and the pan-caspase inhibitor ZVAD-FMK did not protect against SAHA. Conversely, poly(ADP)ribose polymerase (PARP) was cleaved in a pattern indicative of calpain activation, and the calpain inhibitor calpeptin abrogated SAHA-induced cell death. Importantly, SAHA sensitized MMAS cells to death receptor-mediated apoptosis and inhibited the secretion of interleukin 6 (IL-6) induced in bone marrow stromal cells (BMSCs) by binding of MM cells, suggesting that it can overcome cell adhesion-mediated drug resistance. Our studies delineate the mechanisms whereby HDAC inhibitors mediate anti-MM activity and overcome drug resistance in the BM milieu and provide the framework for clinical evaluation of SAHA, which is bioavailable, well tolerated, and bioactive after oral administration, to improve patient outcome. (C) 2003 by The American Society of Hematology.