Sirt1 deacetylates c-Myc and promotes c-Myc/Max association

• Published in: The international journal of biochemistry & cell biology 2011-11, Vol.43 (11), p.1573-1581
• Main Authors: Mao, Beibei, Zhao, Guowei, Lv, Xiang, Chen, Hou-Zao, Xue, Zheng, Yang, Ben, Liu, De-Pei, Liang, Chih-Chuan
• Format: Article
• Language: English
• Subjects: Acetylation; Activation; apoptosis; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors - genetics; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors - metabolism; Biological; c-Myc; carcinogenesis; Cell Cycle Checkpoints; Cell Differentiation - genetics; Cell Proliferation; Cell Transformation, Neoplastic - genetics; Cell Transformation, Neoplastic - metabolism; Gene expression; histone deacetylase; Histones; Human; Humans; Immunoprecipitation; Inhibitors; K562 Cells; Leukemia, Erythroblastic, Acute - genetics; Leukemia, Erythroblastic, Acute - metabolism; Leukemias; Max; neoplasm cells; neoplasms; oncogene proteins; Plasmids; post-translational modification; Proliferation; Promoter Regions, Genetic; Protein Binding; Protein Processing, Post-Translational; Protein Structure, Tertiary; Proto-Oncogene Proteins c-myc - genetics; Proto-Oncogene Proteins c-myc - metabolism; RNA interference; Signal Transduction - genetics; Sirt1; Sirtuin 1 - genetics; Sirtuin 1 - metabolism; Surgical implants; transcription factors; Transcriptional Activation; Transfection
• ISSN: 1357-2725; 1878-5875
• DOI: 10.1016/j.biocel.2011.07.006

The c-Myc oncoprotein plays critical roles in multiple biological processes by controlling cell proliferation, apoptosis, differentiation, and metabolism. Especially, c-Myc is frequently overexpressed in many human cancers and widely involved in tumorigenesis. However, how the post-translational modifications, especially acetylation of c-Myc, contribute to its activity in the leukemia cells remains largely unknown. Sirt1, a NAD-dependent class III histone deacetylase, has a paradoxical role in tumorigenesis by deacetylating several transcription factors, including p53, E2F1 and forkhead proteins. In this study, we show that Sirt1 interacts physically with the C-terminus of c-Myc and deacetylates c-Myc both in vitro and in vivo. Moreover, the deacetylation of c-Myc by Sirt1 promotes its association with Max, a partner essential for its activation, thereby facilitating c-Myc transactivation activity on hTERT promoter. Finally, inhibition of endogenous Sirt1 in K562 cells by either RNAi or its inhibitor NAM causes the overall decrease of c-Myc target genes expression, including hTERT, cyclinD2 and LDHA, which further suppress cell proliferation and arrest cell cycle at G1/S phase. Thus, our results demonstrate the positive effect of Sirt1 on c-Myc activity by efficiently enhancing c-Myc/Max association in human leukemia cell line K562, suggesting a potential role of Sirt1 in tumorigenesis.