HDAC10 promotes lung cancer proliferation via AKT phosphorylation.
HDAC10 promotes lung cancer proliferation via AKT phosphorylation.
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HDAC10 通过 AKT 磷酸化促进肺癌增殖。
DOI：
10.18632/oncotarget.10673
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发表时间：
2016-09-13
期刊：
影响因子：
--
通讯作者：
Kang J
中科院分区：
文献类型：
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作者：
Yang Y;Huang Y;Wang Z;Wang HT;Duan B;Ye D;Wang C;Jing R;Leng Y;Xi J;Chen W;Wang G;Jia W;Zhu S;Kang J
组蛋白去乙酰化酶10（HDAC 10）是II类HDACs的成员，其在癌症中的作用正在显现。在本研究中，我们发现HDAC 10在肺癌组织中高度表达。它主要存在于肺癌细胞的细胞质中，但存在于相邻正常细胞的细胞核中。进一步的研究表明，HDAC 10存在于多种肺癌细胞系的细胞质中，包括A549、H358和H460细胞系，但主要存在于正常肺上皮16 HBE细胞的细胞核中。一个富含亮氨酸的基序R505 L506 L507 C508 V509 A510 L511被鉴定为其核定位信号（NLS），并且发现一个突变体（Mut-505-511）在其原始的R和L位置处均突变为A，是核定位缺陷的。功能分析显示HDAC 10促进肺癌细胞生长，其敲低诱导细胞周期阻滞和凋亡。机制研究表明，HDAC 10敲低显着降低AKT的Ser 473的磷酸化，AKT的表达显着拯救HDAC 10敲低引起的细胞周期停滞和凋亡。免疫共沉淀试验表明，HDAC 10与AKT相互作用，抑制HDAC 10活性可降低其与AKT的相互作用和AKT的磷酸化。最后，我们证实HDAC 10在小鼠模型中促进肺癌增殖。我们的研究表明，HDAC 10定位于肺癌细胞的细胞质中并发挥作用，从而强调了其在肺癌诊断和治疗中的潜在作用。
Histone deacetylase 10 (HDAC10) is a member of the class II HDACs, and its role in cancer is emerging. In this study, we found that HDAC10 is highly expressed in lung cancer tissues. It resides mainly in the cytoplasm of lung cancer cells but resides in the nucleus of adjacent normal cells. Further examinations revealed that HDAC10 resides in the cytoplasm in multiple lung cancer cell lines, including the A549, H358 and H460 cell lines, but mainly resides in the nucleus of normal lung epithelial 16HBE cells. A leucine-rich motif, R505L506L507C508V509A510L511, was identified as its nuclear localization signal (NLS), and a mutant (Mut-505-511) featuring mutations to A at each of its original R and L positions was found to be nuclear-localization defective. Functional analysis revealed that HDAC10 promoted lung cancer cell growth and that its knockdown induced cell cycle arrest and apoptosis. Mechanistic studies showed that HDAC10 knockdown significantly decreased the phosphorylation of AKT at Ser473 and that AKT expression significantly rescued the cell cycle arrest and apoptosis elicited by HDAC10 knockdown. A co-immunoprecipitation assay suggested that HDAC10 interacts with AKT and that inhibition of HDAC10 activity decreases its interaction with and phosphorylation of AKT. Finally, we confirmed that HDAC10 promoted lung cancer proliferation in a mouse model. Our study demonstrated that HDAC10 localizes and functions in the cytoplasm of lung cancer cells, thereby underscoring its potential role in the diagnosis and treatment of lung cancer.