Human arrest defective 1 acetylates and activates beta-catenin, promoting lung cancer cell proliferation.
Arrest defective 1 (ARD1), an acetyltransferase, is essential for the yeast life cycle. Although its human homologue (hARD1) has been identified, its biological functions in human cells remain unclear. In the present study, we examined the biological function of hARD1. In H1299 and A549 lung cancer cells, hARD1-silencing RNA inhibited cell proliferation and induced G(1) arrest. Cyclin D1 was also found to be down-regulated in these growth-arrested cells, and the ectopic expression of cyclin D1 rescued cell growth. hARD1 knockdown repressed the promoter activity of the cyclin D1 gene, which inhibited the transcription of cyclin D1. Moreover, hARD1 knockdown reduced the binding of beta-catenin/TCF4 transcription factor to cyclin D1 promoter and repressed its transcriptional activity. Inversely, hARD1 expression increased the transcriptional activity of beta-catenin. Both endogenous and ectopically expressed hARD1 was coimmunoprecipitated with beta-catenin. hARD1 knockdown did not affect beta-catenin expression or degradation but noticeably reduced acetylated beta-catenin. The beta-catenin binding and acetylation by hARD1 were observed in vitro. Therefore, it is suggested that hARD1 participates in proliferation of lung cancer cells via the activation of beta-catenin.
Lim
Ji-Hong
JH
Cancer Research Institute and Departments of Pharmacology and Physiology, Seoul National University College of Medicine, Seoul, Korea.
Park
Jong-Wan
JW
Chun
Yang-Sook
YS
D000107:Acetylation; D000123:Acetyltransferases / Q000235:genetics / Q000378:metabolism*; D002289:Carcinoma, Non-Small-Cell Lung / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D048708:Cell Growth Processes / Q000502:physiology; D045744:Cell Line, Tumor; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism; D016193:G1 Phase / Q000502:physiology; D006801:Humans; D008175:Lung Neoplasms / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D063209:N-Terminal Acetyltransferase A; D063213:N-Terminal Acetyltransferase E; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D034741:RNA, Small Interfering / Q000235:genetics; D051820:TCF Transcription Factors / Q000378:metabolism; D058118:Transcription Factor 7-Like 2 Protein; D051176:beta Catenin / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
D034741:RNA, Small Interfering; D051820:TCF Transcription Factors; C544894:TCF7L2 protein, human; D058118:Transcription Factor 7-Like 2 Protein; D051176:beta Catenin; D019938:Cyclin D1; D000123:Acetyltransferases; D063209:N-Terminal Acetyltransferase A; C504824:NAA10 protein, human; D063213:N-Terminal Acetyltransferase E