Histone deacetyltransferase inhibitors Trichostatin A and Mocetinostat differentially regulate MMP9, IL-18 and RECK expression, and attenuate Angiotensin II-induced cardiac fibroblast migration and proliferation

Abstract

Histone acetylation/deacetylation plays a key role in the epigenetic regulation of multiple pro-fibrotic genes. Here we investigated the effects of histone deacetyltransferase (HDAC) inhibition on angiotensin (Ang)-II-induced pro-fibrotic changes in adult mouse cardiac fibroblasts (CF). CF express class I HDACs 1 and 2, and Ang-II induces their activation. Notably, silencing HDAC1 or HDAC2 attenuated Ang-II induced CF proliferation and migration. Under basal conditions, HDAC1 dimerizes with HDAC2 in CF and Ang-II reversed this interaction. Treatment with Trichostatin A (TSA), a broad-spectrum HDAC inhibitor, restored their physical association, and attenuated Ang-II-induced MMP9 expression, IL-18 induction, and extracellular matrix (collagen I, collagen III and fibronectin) production. Further, TSA inhibited Ang-II-induced MMP9 and Il18 transcription by blocking NF-κB and AP-1 binding to their respective promoter regions. By inhibiting Sp1 binding to RECK promoter, TSA reversed Ang-II-induced RECK suppression, collagen and fibronectin expression, and CF migration and proliferation. The class I-specific HDAC inhibitor Mocetinostat (MGCD) recapitulated TSA effects on Ang-II-treated CF. Together, these results demonstrate that targeting HDACs attenuates the pro-inflammatory and pro-fibrotic effects of Ang-II on CF.

HDAC Inhibitors and RECK Modulate Endoplasmic Reticulum Stress in Tumor Cells

“…HDAC inhibitors can induce ER stress to cause cell death in cancers [7,16,18,27]. In addition, HDAC inhibitors have been found to up-regulate RECK expression by preventing HDAC binding to the SP1 site of the RECK promoter [39,40,41,44,45,47]. RECK was found to colocalize with GRP78 to modulate ER stress by binding to and sequestering GRP78.…”

“…Histone acetylation/deacetylation plays a key role in the epigenetic regulation of multiple genes [44]. RECK expression is frequently silenced in aggressive tumor cells by HDAC, and suppressed by HER-2/neu and RAS also through a histone deacetylation mechanism [39,40,41,44,45].…”

“…RECK expression is frequently silenced in aggressive tumor cells by HDAC, and suppressed by HER-2/neu and RAS also through a histone deacetylation mechanism [39,40,41,44,45]. The amount or activity of extracellular matrix-degrading enzymes such as MMPs can be modulated by regulating RECK or at the transcriptional and translational levels using HDAC inhibitors [46].…”

“…The amount or activity of extracellular matrix-degrading enzymes such as MMPs can be modulated by regulating RECK or at the transcriptional and translational levels using HDAC inhibitors [46]. In contrast, RECK expression can be restored by suppressing HDAC with HDAC inhibitors or siRNA [31,39,44,45,46]. Hypoxia-induced down-regulation of RECK is also abolished by knockdown of HDAC1 with siRNA [42].…”

“…Further, HDAC inhibitors such as TSA can up-regulate RECK via transcriptional activation in CL-1 human lung cancer cells, as well as rescue hypoxia-suppressed RECK expression in the H-Ras-transformed human breast MCF10A and HT1080 human fibrosarcoma cell lines [31,45]. TSA antagonizes the inhibitory action of Ras on RECK and reverses angiotensin-II-induced RECK suppression by inhibiting Sp1 binding to the RECK promoter [39,44]. Apicidin, which is also a HDAC inhibitor, markedly decreases HDAC4 expression, blocks cell migration and invasion of human ovarian cancer SKOV-3 cells, and suppresses the growth of SKOV-3 xenografts [47].…”