MYC directs transcription of MCL1 and eIF4E genes to control sensitivity of gastric cancer cells toward HDAC inhibitors
MYC directs transcription of MCL1 and eIF4E genes to control sensitivity of gastric cancer cells toward HDAC inhibitors
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DOI：
10.4161/cc.20008
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发表时间：
2012-04-15
期刊：
影响因子：
4.3
通讯作者：
Schneider, Guenter
中科院分区：
文献类型：
--
作者：
Labisso, Wajana L.;Wirth, Matthias;Schneider, Guenter
组蛋白脱乙酰酶(HDAC)控制着细胞增殖和分化等基本生理过程。HDAC抑制剂(HDACi)可诱导肿瘤细胞周期停滞和凋亡。因此，它们代表了前景看好的癌症疗法，在联合疗法中似乎特别有用。虽然HDACi在目前的临床试验中得到了测试，但调节细胞对HDACi反应的分子机制还不完全清楚。为了深入了解限制HDACi在胃癌中的疗效的途径，我们用临床上相关的HDACi Suberoylanilide异羟肟酸(SAHA)处理了一组胃癌细胞。我们报告了抗凋亡的BCL2家族成员MCL1和BCLXL在SAHA的高抑制浓度(IC50)值的细胞中检测到较高的表达水平。利用RNAi，我们发现MCL1和BCLXL降低了SAHA的疗效。为了找到干扰MCL1和BCLXL表达的策略，我们研究了这两种蛋白的分子调控。我们发现，针对c-myc的特异性siRNA以及对这种与癌症相关的转录因子的药物抑制，降低了MCL1和BCLXL的表达。随后，我们观察到SAHA疗效的增加。我们的数据进一步证明，两种不同的分子机制负责这些因素的调节。C-MYC直接控制MCL1的转录，而BCLXL的调控是由于c-MYC对eIF4E基因的调控能力，而eIF4E基因编码真核翻译的限速因子。我们的数据揭示了c-myc如何控制细胞自主凋亡的新的分子机制，并为协同抑制HDAC和c-myc在胃癌中的作用提供了理论基础。
Histone deacetylases (HDACs) control fundamental physiological processes such as proliferation and differentiation. HDAC inhibitors (HDACi) induce cell cycle arrest and apoptosis of tumor cells. Therefore, they represent promising cancer therapeutics that appear particularly useful in combination therapies. Although HDACi are tested in current clinical trials, the molecular mechanisms modulating the cellular responses toward HDACi are incompletely understood. To gain insight into pathways that limit HDACi efficacy in gastric cancer, we treated a panel of gastric cancer cells with the clinically relevant HDACi suberoylanilide hydroxamic acid (SAHA). We report that higher expression levels of the anti-apoptotic BCL2 family members MCL1 and BCLXL were detectable in cells with high inhibitory concentration 50 (IC50) values for SAHA. Using RNAi, we show that MCL1 and BCLXL lower the efficacy of SAHA. To find strategies to interfere with MCL1 and BCLXL expression, we investigated molecular regulation of both proteins. We show that specific siRNAs against c-MYC as well as pharmacological inhibition of this cancer-relevant transcription factor reduced MCL1 and BCLXL expression. Subsequently, we observed an increase in SAHA efficacy. Our data furthermore demonstrate that two different molecular mechanisms are responsible for the modulation of these factors. Whereas c-MYC controls transcription of MCL1 directly, regulation of BCLXL was due to c-MYC's capability to regulate the eIF4E gene, which encodes a rate-limiting factor of eukaryotic translation. Our data reveal a new molecular mechanism for how c-MYC controls cell autonomous apoptosis and provide a rationale for a concerted inhibition of HDACs and c-MYC in gastric cancer.