title: Acetylation of FOXM1 is essential for its transactivation and tumor growth stimulation.
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.
authors.affiliation: Research Center on Aging, Department of Biochemistry and Molecular Biology, Peking University Health Science Center, Beijing, China.
authors.forename: Cuicui
authors.initials: C
authors.lastname: Lv
authors.affiliation: Research Center on Aging, Department of Biochemistry and Molecular Biology, Peking University Health Science Center, Beijing, China.
authors.forename: Ganye
authors.initials: G
authors.lastname: Zhao
authors.affiliation: Research Center on Aging, Department of Biochemistry and Molecular Biology, Peking University Health Science Center, Beijing, China.
authors.forename: Xinpei
authors.initials: X
authors.lastname: Sun
authors.affiliation: Research Center on Aging, Department of Biochemistry and Molecular Biology, Peking University Health Science Center, Beijing, China.
authors.forename: Pan
authors.initials: P
authors.lastname: Wang
authors.affiliation: Research Center on Aging, Department of Biochemistry and Molecular Biology, Peking University Health Science Center, Beijing, China.
authors.forename: Nan
authors.initials: N
authors.lastname: Xie
authors.affiliation: Center for Medical Genetics, Department of Medical Genetics, Peking University Health Science Center, Beijing, China.
authors.forename: Jianyuan
authors.initials: J
authors.lastname: Luo
authors.affiliation: Research Center on Aging, Department of Biochemistry and Molecular Biology, Peking University Health Science Center, Beijing, China.
authors.forename: Tanjun
authors.initials: T
authors.lastname: Tong
mesh_terms: D000107:Acetylation; D000818:Animals; D002453:Cell Cycle; D005260:Female; D000072278:Forkhead Box Protein M1 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009369:Neoplasms / Q000378:metabolism* / Q000473:pathology; D055550:Protein Stability; D056564:Sirtuin 1 / Q000378:metabolism*; D015533:Transcriptional Activation; D023041:Xenograft Model Antitumor Assays; D050880:p300-CBP Transcription Factors / Q000378:metabolism*; D000099224:p300-CBP-Associated Factor
chemical_list: D000072278:Forkhead Box Protein M1; D056564:Sirtuin 1; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor; C107585:FOXM1 protein, human; C447939:SIRT1 protein, human
keywords: FOXM1; SIRT1; acetylation; cell cycle; tumor