# 4-hexylIncorinol Inhibits Class I Histone Deacetylases in Human Umbilical Cord Endothelial Cells
###### Abstract  
Histone deacetylases (HDACs) are key enzymes for post-translational modification and influence on various cellular activities. Thus, HDACs are associated with many diseases and their inhibitors have clinical significance. Here, 4-hexylIncorional (4 HR) was studied as an inhibitor for class I HDACs using the HDAC inhibitor (HDACci) Trichostatin-A as a positive control. The 4 HR was administered 1-100 \(\upmu\)M to human umbilical endothelial cells (HUVECs) and the HDAC expression and activity were examined. The 4 HR decreased the expression level of HDAC1, 3, 4, and 5 in a time and dose-dependent manner. The 4 HR also increased acetylated lysine and decreased HDAC activity significantly (_p_ < 0.05). Collectively, 4 HR was a new class I HDAC inhibitor that reduced the expression and activity of HDAC in HUVECs. 4-hexylIncorionol; histone deacetylase; mitochondria; ATP +
Footnote †: journal:  
in pancreatic cancer [6]. The overexpression of HDAC2 is also observed in pathologic cardiomegaly [7]. A representative broad-spectrum HDAC inhibitor (HDACi)-trichostatin A (TSA) inhibits cardiac hypertrophy [8]. TSA is also used for the treatment of established cardiac hypertrophy [9]. The administration of HDACi is helpful for muscle regeneration in muscle dystrophy [10]. Valproic acid was originally developed as an anti-convulsant and HDACi. Valproic acid improves nerve regeneration and motor function in the damaged rat model [11]. TSA treats rheumatism by suppressing the expression level of tumor necrosis factor-\(\alpha\) (TNF-\(\alpha\)) and interleukin-6 (IL-6) [12]. Butyrate is an organic chemical of bacterial origin and HDACi [13]. The administration of butyrate reduces pain in epileptic rats [13] and inhibits the proliferation of colorectal cancer cells [4]. HDAC: histone deacetylase, SIRT: sirtuin. Resorcinolic lipid is an organic chemical of bacterial origin [14]. The substance 4-Hexylresorcinol (4 HR) is a synthetic resorcinolic lipid and has been developed as an antiseptic agent [14]. The 4 HR suppresses the respiration of micro-organisms and induces dormancy [15]. The long alkyl group of 4 HR binds to tyrosinase effectively and inhibits enzyme activity [16]. Accordingly, 4 HR can be used to prevent melanosis of food [16]. As it is considered as a food additive, toxicological studies have been widely done. In these studies, anticancer effects have been found [17; 18]. Based on these results, the detailed anticancer mechanisms of 4 HR have been investigated [19; 20]. The 4 HR suppresses the nuclear factor-\(\kappa\)B (NF-\(\kappa\)B) pathway by inhibiting transglutaminase-2 (TG-2) in oral cancer cells [19; 21]. Unlike oral cancer cells, 4 HR administration reduces the formation of foreign body giant cells in the silk-based graft material [22] and suppresses TNF-\(\alpha\) expression in a deep burn [23]. Recently, 4 HR has been identified as a potent M2 macrophage polarizing agent [24]. Transforming growth factor-\(\beta\)1 (TGF-\(\beta\)1) is increased by 4 HR, while decreasing TNF-\(\alpha\) expression in RAW263.7 cells [25], and the expression level of vascular endothelial cell growth factor (VEGF) is increased by 4 HR via the TGF-\(\beta\)1 mediated pathway in human umbilical endothelial cells (HUVECs) [26]. During investigation of the mechanism of TGF-\(\beta\)1 expression by 4 HR administration, we found that the broad function of 4 HR might be similar to that of HDACi. The 4 HR has a hydrophobic alkyl group [14] and the length of the alkyl group is similar to that of the functional group in other HDACi [27]. Though 4 HR does not have an acetyl group at the end of the hexyl group, hydroxyl-benzene can do the role as a cap group. Therefore, the possibility of HDACi for 4 HR is highly probable. The purposes of this study were to clarify 4 HR as Class I HDACi in HUVECs. Class I HDACi (HDAC1 and 3) and class IIA HDACi (HDAC4 and 5) expression levels and acetylated lysine level were evaluated by Western blot.