Roles of achaete-scute homologue 1 in DKK1 and E-cadherin repression and neuroendocrine differentiation in lung cancer.
The proneural basic-helix-loop-helix protein achaete-scute homologue 1 (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 beta1 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.
Osada
Hirotaka
H
Division of Molecular Oncology, Aichi Cancer Center Research Institute, Nagoya 464-8681, Japan. hosada@aichi-cc.jp
Tomida
Shuta
S
Yatabe
Yasushi
Y
Tatematsu
Yoshio
Y
Takeuchi
Toshiyuki
T
Murakami
Hideki
H
Kondo
Yutaka
Y
Sekido
Yoshitaka
Y
Takahashi
Takashi
T
D048868:Adaptor Proteins, Signal Transducing; D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D015820:Cadherins / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D018278:Carcinoma, Neuroendocrine / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D018288:Carcinoma, Small Cell / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002454:Cell Differentiation / Q000502:physiology; D045744:Cell Line, Tumor; D018925:Chemokines; D019175:DNA Methylation; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D015536:Down-Regulation; D020869:Gene Expression Profiling; D020868:Gene Silencing; D011495:Histone-Lysine N-Methyltransferase; D006801:Humans; D019012:Integrin beta1 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D011401:Promoter Regions, Genetic; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*
D048868:Adaptor Proteins, Signal Transducing; D015820:Cadherins; D018925:Chemokines; C501126:DKK1 protein, human; C498624:DKK3 protein, human; D004268:DNA-Binding Proteins; D019012:Integrin beta1; D036341:Intercellular Signaling Peptides and Proteins; D014157:Transcription Factors; C490911:ASH1L protein, human; D011495:Histone-Lysine N-Methyltransferase