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Human Arrest Defective 1 Acetylates and Activates ß-Catenin, Promoting Lung Cancer Cell Proliferation

¹ Cancer Research Institute and Departments of ² Pharmacology and ³ Physiology, Seoul National University College of Medicine, Seoul, Korea

Requests for reprints: Yang-Sook Chun, Department of Physiology, Seoul National University College of Medicine, 28 Yongon-dong, Chongno-gu, Seoul 110-799, Korea. Phone: 82-2-3668-7939; Fax: 82-2-745-7996; E-mail: chunys{at}snu.ac.kr.

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 G₁ 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 ß-catenin/TCF4 transcription factor to cyclin D1 promoter and repressed its transcriptional activity. Inversely, hARD1 expression increased the transcriptional activity of ß-catenin. Both endogenous and ectopically expressed hARD1 was coimmunoprecipitated with ß-catenin. hARD1 knockdown did not affect ß-catenin expression or degradation but noticeably reduced acetylated ß-catenin. The ß-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 ß-catenin. (Cancer Res 2006; 66(22): 10677-82)

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