Affiliation:
1. Department of Molecular Oncology, Moffitt Cancer Center, Tampa, Florida, USA
Abstract
ABSTRACT
Histone deacetylase (HDAC) inhibition leads to cell cycle arrest in G
1
and G
2
, 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 G
2
/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.
Publisher
American Society for Microbiology
Subject
Cell Biology,Molecular Biology
Cited by
59 articles.
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