Oncotarget

Research Papers:

Acetylation of FOXM1 is essential for its transactivation and tumor growth stimulation

Cuicui Lv, Ganye Zhao, Xinpei Sun, Pan Wang, Nan Xie, Jianyuan Luo and Tanjun Tong _

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Oncotarget. 2016; 7:60366-60382. https://doi.org/10.18632/oncotarget.11332

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Abstract

Cuicui Lv1, Ganye Zhao1, Xinpei Sun1, Pan Wang1, Nan Xie1, Jianyuan Luo2, Tanjun Tong1

1Research Center on Aging, Department of Biochemistry and Molecular Biology, Peking University Health Science Center, Beijing, China

2Center for Medical Genetics, Department of Medical Genetics, Peking University Health Science Center, Beijing, China

Correspondence to:

Tanjun Tong, email: ttj@bjmu.edu.cn

Jianyuan Luo, email: luojianyuan@bjmu.edu.cn

Keywords: FOXM1, SIRT1, acetylation, cell cycle, tumor

Received: March 27, 2016    Accepted: July 10, 2016    Published: August 17, 2016

ABSTRACT

Forkhead box transcription factor M1 (FOXM1) plays crucial roles in a wide array of biological processes, including cell proliferation and differentiation, the cell cycle, and tumorigenesis by regulating the expression of its target genes. Elevated expression of FOXM1 is frequently observed in a multitude of malignancies. Here we show that FOXM1 can be acetylated by p300/CBP at lysines K63, K422, K440, K603 and K614 in vivo. This modification is essential for its transactivation on the target genes. Acetylation of FOXM1 increases during the S phase and remains high throughout the G2 and M phases, when FOXM1 transcriptional activity is required. We find that the acetylation-deficient FOXM1 mutant is less active and exhibits significantly weaker tumorigenic activities compared to wild-type FOXM1. Mechanistically, the acetylation of FOXM1 enhances its transcriptional activity by increasing its DNA binding affinity, protein stability, and phosphorylation sensitivity. In addition, we demonstrate that NAD-dependent histone deacetylase SIRT1 physically binds to and deacetylates FOXM1 in vivo. The deacetylation of FOXM1 by SIRT1 attenuates its transcriptional activity and decreases its protein stability. Together, our findings demonstrate that the reversible acetylation of FOXM1 by p300/CBP and SIRT1 modulates its transactivation function.


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