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.
Highlights
Forkhead Box M1 (FOXM1) belongs to a large family of Forkhead box (Fox) transcription factors that all share an evolutionarily conserved Forkhead/winged helix DNA-binding domain [1,2,3]
It has been shown that the CREB binding protein (CBP)/p300 acetyltransferases can be recruited to the C-terminal region of FOXM1 and enhance its transcriptional activity at specific stages of the cell cycle [23]
A wide range of non-histone transcription factors have been described to be modified by acetylation recently [41,42,43,44,45,46], so we investigated whether FOXM1 is acetylated by CBP/ p300 in a cellular condition
Summary
Forkhead Box M1 (FOXM1) belongs to a large family of Forkhead box (Fox) transcription factors that all share an evolutionarily conserved Forkhead/winged helix DNA-binding domain [1,2,3]. It activates a wide range of target genes by binding to the consensus sequence, TAAACA [4]. FOXM1 is a key regulator for G1/S and G2/M transitions, and M phase progression It induces the expression of cyclin A2, JNK1, ATF2, Skp, Cks, and Cdc25A to promote the G1/S transition [9, 10]. FOXM1-deficient hepatocytes in mice fail to proliferate and are resistant to the development of hepatic tumors when induced with xenobiotic liver carcinogens [13, 14]
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