Regulation of the HIF-1α stability by histone deacetylases

Abstract

Histone deacetylase inhibitors (HDACIs) are currently in clinical trials partly due to their potent antiangiogenic effects. However, the detailed mechanism of their action is unclear. Here, we observed that several HDACIs (TSA, SB, Apicidin, and VPA) dramatically decreased HIF-1• protein level and transcriptional activity of HIF-1 in human and mouse tumor cell lines. Furthermore, class I HDACs, HDAC1 and 3 enhanced HIF-1• stability and HIF-1 transactivation function in hypoxic conditions. In addition, immunoprecipitation and in vitro binding assays revealed that HDAC1 and 3 directly bind to the oxygen-dependent degradation domain of HIF-1•. Collectively, these results suggest that HDAC1 and 3 are considered as a positive regulator of HIF-1• stability via direct interaction and may play an important role in HIF-1-induced tumor angiogenesis.

Histone Deacetylase 7 Promotes Toll-like Receptor 4-dependent Proinflammatory Gene Expression in Macrophages

“…Our data thus suggest that multiple Hdacs are involved in regulating HIF-1␣ during TLR4 responses, non-class IIa Hdacs being required for the initial LPSinduced expression of this protein, whereas Hdac7-u subsequently promotes HIF-1␣-dependent transcription. Although a number of HDACs are known to regulate HIF-1␣ (38,49,50), to the best of our knowledge, this is the first report of HDAC-dependent regulation of HIF-1␣ in TLR pathways.…”

Cutaneous T‐cell lymphoma: 2011 update on diagnosis, risk‐stratification, and management

“…The 18 human HDACs may be classified as either zinc-or NAD 1 -dependent and further subclassified into class I (HDAC1, 2, 3, and 8), class II (HDAC4, 5, 6, 7, 9, and 10), class III (including NAD 1 -dependent sirtuins), and class IV (HDAC11) HDACs. As HDACs regulate a wide variety of processes involved in carcinogenesis, multiple mechanisms may explain the clinical activity of HDAC inhibitors [249,250], including altered gene expression of cell-cycle and apoptotic regulatory proteins [251][252][253][254][255], acetylation of nonhistone proteins regulating cell growth and survival [256][257][258][259], angiogenesis [260,261], aggresome formation [262], and DNA repair [263]. In addition, HDAC inhibitors may have important effects on the tumor microenvironment via reactive oxygen species [264,265], enhanced antigen presentation [266] and downregulation of immunomodulatory cytokines, like IL-10 [267].…”

Histone Deacetylase Inhibitors: Overview and Perspectives

“…1,[5][6][7][8][9][10][11][12][13][14][15][16][17]. Knockout analysis of different class I and class II HDAC proteins indicates that class I HDACs play a role in cell survival and proliferation, whereas class II HDACs may have tissue-specific roles.…”