Histone deacetylase inhibitors induce apoptosis in myeloid leukemia by suppressing autophagy.
Histone deacetylase inhibitors induce apoptosis in myeloid leukemia by suppressing autophagy.
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组蛋白脱乙酰酶 (HDAC) 抑制剂 (HDACis) 是一种经过充分表征的抗癌药物，在临床试验中取得了良好的结果。然而，从机制上讲，人们对它们在杀死恶性细胞而不伤害正常细胞方面的选择性知之甚少。基于基因表达的化学基因组学发现 HDACis 对唐氏综合症相关骨髓性白血病 (DS-AMKL) 母细胞特别有效。研究 HDACis 的抗白血病功能揭示了它们对关键自噬蛋白（包括 ATG7）的转录和翻译后调节。这会导致自噬的抑制，自噬是一种溶酶体降解过程，可以保护细胞免受损坏或不必要的细胞器和蛋白质聚集体的影响。 DS-AMKL 细胞由于 mTOR 激活而表现出低基线自噬。因此，HDAC 抑制将自噬抑制到临界阈值以下，从而导致线粒体积累、活性氧产生、DNA 损伤和细胞凋亡。这些 HDACi 介导的作用可能会在自噬激活后恢复，或在进一步的药理学或遗传抑制后加剧。我们的研究结果进一步扩展到基础自噬水平较低的其他主要急性髓系白血病亚组。 mTOR 激活对自噬的组成性抑制代表了癌症和正常细胞之间的固有差异。因此，通过自噬抑制，HDACs 剥夺了细胞重要的促生存机制，这转化为一种有吸引力的特异性靶向癌细胞的策略。
Histone deacetylase (HDAC)-inhibitors (HDACis) are well characterized anti-cancer agents with promising results in clinical trials. However, mechanistically little is known regarding their selectivity in killing malignant cells while sparing normal cells. Gene expression-based chemical genomics identified HDACis as being particularly potent against Down syndrome associated myeloid leukemia (DS-AMKL) blasts. Investigating the anti-leukemic function of HDACis revealed their transcriptional and posttranslational regulation of key autophagic proteins, including ATG7. This leads to suppression of autophagy, a lysosomal degradation process that can protect cells against damaged or unnecessary organelles and protein aggregates. DS-AMKL cells exhibit low baseline autophagy due to mTOR activation. Consequently, HDAC inhibition repressed autophagy below a critical threshold, which resulted in accumulation of mitochondria, production of reactive oxygen species, DNA-damage and apoptosis. Those HDACi-mediated effects could be reverted upon autophagy activation or aggravated upon further pharmacological or genetic inhibition. Our findings were further extended to other major acute myeloid leukemia subgroups with low basal level autophagy. The constitutive suppression of autophagy due to mTOR activation represents an inherent difference between cancer and normal cells. Thus, via autophagy suppression, HDACis deprive cells of an essential pro-survival mechanism, which translates into an attractive strategy to specifically target cancer cells.
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影响因子：
82.9
作者：
Janes, Matthew R.;Limon, Jose J.;So, Lomon;Chen, Jing;Lim, Raymond J.;Chavez, Melissa A.;Vu, Collin;Lilly, Michael B.;Mallya, Sharmila;Ong, S. Tiong;Konopleva, Marina;Martin, Michael B.;Ren, Pingda;Liu, Yi;Rommel, Christian;Fruman, David A.
通讯作者：
Fruman, David A.
影响因子：
56.9
作者：
Choudhary, Chunaram;Kumar, Chanchal;Mann, Matthias
通讯作者：
Mann, Matthias
DOI：
10.1073/pnas.0511150103
发表时间：
2006-02-28
影响因子：
11.1
作者：
Bourquin, JP;Subramanian, A;Orkin, SH
通讯作者：
Orkin, SH
影响因子：
13.3
作者：
Dalby KN;Tekedereli I;Lopez-Berestein G;Ozpolat B
通讯作者：
Ozpolat B
影响因子：
15.9
作者：
Chuang, De-Maw;Leng, Yan;Marinova, Zoya;Kim, Hyeon-Ju;Chiu, Chi-Tso
通讯作者：
Chiu, Chi-Tso