Depletion of histone deacetylase protein: a common consequence of inflammatory cytokine signaling?
The dynamics of histone acetylation and deacetylation have long been known to influence gene expression by cellular signaling pathways. However, the mechanisms that regulate histone acetyl transferases (HATs) and histone deacetylases (HDACs) by these pathways have only recently become the focus of scientific investigation, spurred by increasing knowledge that HDACs can promote cancer growth. We recently reported that pro-inflammatory signals such as tumor necrosis factor alpha (TNFalpha) induce HDAC1 ubiquitination and proteasomal degradation through the IkappaB kinase IKKbeta. The resulting depletion of cellular HDAC1 levels lead to a consequent depletion of HDAC1 associated with the CDKN1A gene promoter and increased expression of its protein product, p21(WAF1/CIP1). This phenomenon heralds a unique mechanism of HDAC regulation that modulates the pro-inflammatory activity of TNFalpha and other cytokines at the level of gene expression. Here we discuss the current knowledge of pro-inflammatory cytokine-induced regulation of gene expression, emphasizing the involvement of HDAC1, and its possible implications in inflammation, cancer, and their therapy.
Gopal
Y N Vashisht
YN
Department of Molecular and Cellular Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030-4009, USA.
Van Dyke
Michael W
MW
D000818:Animals; D005786:Gene Expression Regulation; D056284:Histone Deacetylase 1; D006655:Histone Deacetylases / Q000172:deficiency*; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism; D007249:Inflammation / Q000276:immunology*; D051379:Mice; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D025801:Ubiquitin / Q000378:metabolism
D014409:Tumor Necrosis Factor-alpha; D025801:Ubiquitin; D051550:I-kappa B Kinase; D046988:Proteasome Endopeptidase Complex; C110550:HDAC1 protein, human; D056284:Histone Deacetylase 1; D006655:Histone Deacetylases