Regulation of histone deacetylase 4 expression by the sp family of transcription factors

Fang Liu, Nabendu Pore, Mijin Kim, K. Ranh Voong, Melissa Dowling, Amit Maity, Gary D. Kao

Research output: Contribution to journalArticlepeer-review

Abstract

Histone deacetylases mediate critical cellular functions but relatively little is known about mechanisms controlling their expression, including expression of HDAC4, a class II HDAC implicated in the modulation of cellular differentiation and viability. Endogenous HDAC4 mRNA, protein levels and promoter activity were all readily repressed by mithramycin, suggesting regulation by GC-rich DNA sequences. We validated consensus binding sites for Sp1/Sp3 transcription factors in the HDAC4 promoter through truncation studies and targeted mutagenesis. Specific and functional binding by Sp1/Sp3 at these sites was confirmed with chromatin immunoprecipitation (ChIP) and electromobility shift assays (EMSA). Cotransf ection of either Sp1 or Sp3 with a reporter driven by the HD AC4 promoter led to high activities in SL2 insect cells (which lack endogenous Sp1/Sp3). In human cells, restored expression of Sp1 and Sp3 up-regulated HDAC4 protein levels, whereas levels were decreased by RNA-interference-mediated knockdown of either protein. Finally, variable levels of Sp1 were in concordance with that of HDAC4 in a number of human tissues and cancer cell lines. These studies together characterize for the first time the activity of the HDAC4 promoter, through which Sp1 and Sp3 modulates expression of HDAC4 and which may contribute to tissue or cell-line-specific expression of HDAC4.

Original languageEnglish (US)
Pages (from-to)585-597
Number of pages13
JournalMolecular biology of the cell
Volume17
Issue number2
DOIs
StatePublished - Feb 2006
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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