Roles of achaete-scute homologue 1 in DKK1 and E-cadherin repression and neuroendocrine differentiation in lung cancer
Roles of achaete-scute homologue 1 in DKK1 and E-cadherin repression and neuroendocrine differentiation in lung cancer
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DOI：
10.1158/0008-5472.can-07-5039
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发表时间：
2008-03-15
期刊：
影响因子：
11.2
通讯作者：
Takahashi, Takashi
中科院分区：
文献类型：
--
作者：
Osada, Hirotaka;Tomida, Shuta;Takahashi, Takashi
前膜碱性-螺旋-环-螺旋蛋白-鳞片同源物I （ASH1）以谱系特异性的方式在非常有限的正常细胞和癌细胞中表达，包括正常肺神经内分泌细胞和具有神经内分泌特征的肺癌细胞。我们之前的研究结果表明，ASH1可能在具有神经内分泌特征的肺癌的生长和生存中起着至关重要的作用，这促使我们研究ASH1在其参与致癌过程中的分子功能。本文中，我们首次报道了ASH1作为一种双转录因子，通过激活神经内分泌分化标记物和抑制推定的肿瘤抑制因子来发挥作用。该蛋白通过ash1介导的去乙酰化和抑制DKK1和E-cadherin启动子区域组蛋白H3赖氨酸27 （H3K27me3）的三甲基化，使Wnt/ β -catenin信号、E-cadherin和整合素01的负调节因子DKK1和DKK3失活。此外，与具有神经内分泌特征的肺癌细胞相比，ash1转导的A549腺癌细胞在体外和体内均表现出明显的形态学特征改变，并且在体内生长速度更快。我们的研究结果为更好地理解ASH1在具有神经内分泌特征的肺癌癌变过程中的分子和细胞生物学作用提供了重要线索，并为未来的研究提供了依据，以阐明这种具有双重功能的转录因子的谱系特异性依赖性。
The proneural basic-helix-loop-helix protein achaete-scute homologue I (ASH1) is expressed in a very limited spectrum of normal and cancerous cells in a lineage-specific manner, including normal pulmonary neuroendocrine cells and lung cancer cells with neuroendocrine features. Our previous results indicated that ASH1 may play a crucial role in the growth and survival of lung cancers with neuroendocrine features, which prompted us to investigate the molecular function of ASH1 in relation to its involvement in carcinogenic processes. Herein, we report for the first time that ASH1 functions as a dual transcription factor by activating neuroendocrine differentiation markers and also repressing putative tumor suppressors. This protein was found to inactivate DKK1 and DKK3, negative regulators of Wnt/beta-catenin signaling, E-cadherin, and integrin 01 through ASH1-mediated deacetylation and repressive trimethylation of lysine 27 (H3K27me3) of histone H3 in the promoter regions of DKK1 and E-cadherin. In addition, ASH1-transduced A549 adenocarcinoma cells exhibited markedly altered morphology characteristics compared with lung cancer cells with neuroendocrine features both in vitro and in vivo and also grew faster in vivo. Our results provide important clues for a better understanding of the molecular and cellular biological roles of ASH1 in the process of carcinogenesis of lung cancers with neuroendocrine features and warrant future investigations to shed light on the lineage-specific dependency of this transcription factor with dual functions.