KLF9 is a novel transcriptional regulator of bortezomib- and LBH589-induced apoptosis in multiple myeloma cells
KLF9 is a novel transcriptional regulator of bortezomib- and LBH589-induced apoptosis in multiple myeloma cells
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DOI：
10.1182/blood-2011-04-346676
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发表时间：
2012-02-09
期刊：
影响因子：
20.3
通讯作者：
Nikiforov, Mikhail A.
中科院分区：
文献类型：
--
作者：
Mannava, Sudha;Zhuang, DaZhong;Nikiforov, Mikhail A.
硼替佐米是多发性骨髓瘤（MM）和套细胞淋巴瘤的治疗剂，其抑制蛋白酶体降解，导致细胞转录程序的实质性变化，并最终导致细胞凋亡。硼替佐米诱导MM细胞凋亡所需的转录调节因子在很大程度上是未知的。使用基因表达谱分析，我们确定了36个转录因子，显示与硼替佐米治疗MM细胞的表达改变。对一个临床可用数据库的分析表明，Kruppel样家族因子9（KLF 9）是唯一一个在对硼替佐米有反应的患者MM细胞中基础表达显著高于无反应者的转录因子。我们证明，KLF 9在培养的MM细胞上调硼替佐米，但它不是通过诱导内质网应激。相反，KLF 9水平与组蛋白脱乙酰酶（HDAC）的硼替佐米依赖性抑制相关，并通过HDAC抑制剂LBH 589（帕比司他）增加。此外，硼替佐米诱导内源性KLF 9与促凋亡基因NOXA的启动子结合。重要的是，KLF 9敲低损害了由硼替佐米、LBH 589或这些药物的组合引起的NOXA上调和细胞凋亡，而KLF 9过表达诱导的细胞凋亡部分依赖于NOXA。我们的数据确定KLF 9作为一种新的和潜在的临床相关的药物诱导的MM细胞凋亡的转录调控因子。（血。2012; 119（6）：1450-1458）
Bortezomib, a therapeutic agent for multiple myeloma (MM) and mantle cell lymphoma, suppresses proteosomal degradation leading to substantial changes in cellular transcriptional programs and ultimately resulting in apoptosis. Transcriptional regulators required for bortezomib-induced apoptosis in MM cells are largely unknown. Using gene expression profiling, we identified 36 transcription factors that displayed altered expression in MM cells treated with bortezomib. Analysis of a publically available database identified Kruppel-like family factor 9 (KLF9) as the only transcription factor with significantly higher basal expression in MM cells from patients who responded to bortezomib compared with nonresponders. We demonstrated that KLF9 in cultured MM cells was up-regulated by bortezomib; however, it was not through the induction of endoplasmic reticulum stress. Instead, KLF9 levels correlated with bortezomib-dependent inhibition of histone deacetylases (HDAC) and were increased by the HDAC inhibitor LBH589 (panobinostat). Furthermore, bortezomib induced binding of endogenous KLF9 to the promoter of the proapoptotic gene NOXA. Importantly, KLF9 knockdown impaired NOXA up-regulation and apoptosis caused by bortezomib, LBH589, or a combination of theses drugs, whereas KLF9 overexpression induced apoptosis that was partially NOXA-dependent. Our data identify KLF9 as a novel and potentially clinically relevant transcriptional regulator of drug-induced apoptosis in MM cells. (Blood. 2012; 119(6): 1450-1458)