title: Histone Deacetylase 10 Regulates the Cell Cycle G2/M Phase Transition via a Novel Let-7-HMGA2-Cyclin A2 Pathway.
abstract: Histone deacetylase (HDAC) inhibition leads to cell cycle arrest in G1 and G2, suggesting HDACs as therapeutic targets for cancer and diseases linked to abnormal cell growth and proliferation. Many HDACs are transcriptional repressors. Some may alter cell cycle progression by deacetylating histones and repressing transcription of key cell cycle regulatory genes. Here, we report that HDAC10 regulates the cell cycle via modulation of cyclin A2 expression, and cyclin A2 overexpression rescues HDAC10 knockdown-induced G2/M transition arrest. HDAC10 regulates cyclin A2 expression by deacetylating histones near the let-7 promoter, thereby repressing transcription. In HDAC10 knockdown cells, let-7f and microRNA 98 (miR-98) were upregulated and the let-7 family target, HMGA2, was downregulated. HMGA2 loss resulted in enrichment of the transcriptional repressor E4F at the cyclin A2 promoter. These findings support a role for HDACs in cell cycle regulation, reveal a novel mechanism of HDAC10 action, and extend the potential of HDACs as targets in diseases of cell cycle dysregulation.
authors.affiliation: Department of Molecular Oncology, Moffitt Cancer Center, Tampa, Florida, USA.
authors.forename: Yixuan
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Molecular Oncology, Moffitt Cancer Center, Tampa, Florida, USA.
authors.forename: Lirong
authors.initials: L
authors.lastname: Peng
authors.affiliation: Department of Molecular Oncology, Moffitt Cancer Center, Tampa, Florida, USA ed.seto@moffitt.org.
authors.forename: Edward
authors.initials: E
authors.lastname: Seto
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D056751:Cyclin A2 / Q000378:metabolism*; D059565:G2 Phase Cell Cycle Checkpoints; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D025743:HMGA2 Protein / Q000378:metabolism*; D006367:HeLa Cells; D006655:Histone Deacetylases / Q000502:physiology*; D006801:Humans; D051379:Mice; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D008938:Mitosis; D011401:Promoter Regions, Genetic; D014158:Transcription, Genetic
chemical_list: C503721:CCNA2 protein, human; D056751:Cyclin A2; D025743:HMGA2 Protein; C546084:MIRN98 microRNA, human; D035683:MicroRNAs; C487931:mirnlet7 microRNA, human; C447828:HDAC10 protein, human; D006655:Histone Deacetylases