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  • br Experimental br Results and discussions br Conclusions br


    Results and discussions
    Declaration of interests
    Acknowledgements Financial support from the National Natural Science Foundation of China (21605089 and 81773483), the Ningbo Municipal Natural Science Foundation (2017A610228 and 2018A610217), the Open Subject of State Key Laboratory of Chemo/Biosensing and Chemometrics (2016001), and Zhejiang Provincial Natural Science Foundation of China (LY13B070013) are gratefully acknowledged. This work was also sponsored by K.C. Wong Magna Fund in Ningbo University.
    Introduction Histone acetylation which gives rise to DNA relaxation with a positive influence on transcription can be regulated by histone acetyltransferases (HATs) and histone deacetylases (HDACs) [1]. Among these two kinds of enzymes, HATs can be divided into three groups, including the GNATs (Gcn5 N-acetyltransferases), the MOZ, YBF2, SAS2, and TIP60 proteins (MYSTs) and the orphan HATs [2]. MOF (males absent on the first), a member of the MYST family, was initially found to function by acetylation of histone H4 Lys16 (H4K16ac) in dosage compensation whereby transcription of genes on the single male X-chromosome must be increased two-fold relative to females who have two X-chromosomes [3,4]. HMOF, the homolog of the Drosophila dosage compensation proteins MOF, forms human histone acetyltransferase complex (hMSL) which shows strong specificity for histone H4 lysine 16 in chromatin in vitro and in vivo [5]. HMOF displays quite diverse roles in various nuclear processes and some have also been implicated in carcinogenesis [6]. In comparison to normal tissues, hMOF is overexpressed in different kinds of cancers, such as human oral tongue squamous cell carcinoma (OTSCC), non-small cell lung cancer (NSCLC), colon cancer, and thymic lymphoma [7,8]. In OTSCC, hMOF enhanced OSTCC growth by targeting EZH2 [9]. In lung cancer (+)-Usniacin mg A549 and H1299, hMOF RNAi reduced the migration and adhesion. In addition, genes involved in cell proliferation, adhesion and migration like SKP2, ETS1 and ITAG2 were down-regulated. SKP2 is a subunit of SKP1-CUL1-F-box ubiquitin ligase complex that involved in regulation of G1 to S phase transition. The complex is also a positive regulator of proliferation [10]. Further experiments proved that hMOF promoted S phase entry via SKP2 in H1299 cells [8]. Another study revealed that hMOF mediated acetylation increased Nrf2 and its downstream genes and led to large tumor size, advanced disease stage and poor prognosis in NSCLC patients [11]. In breast cancer, MOF acetylated oncogene AIB1 and enhanced its function in promoting breast cancer cells [12]. Besides, in Hela cells, oncogene HOXA9, UCP2, KIAA0657, and HIP1 were down-regulated when cells were transfected with hMOF-specific siRNAs. Moreover, MOF depletion results in decreased cell numbers post-irradiation in SL-2 cells [13]. H4K16 acetylation had close relevance with breast cancer and colon cancer [14]. Analogs of SFN could sensitize HCT116 cells via modulate HAT/HDAC activities and associate DNA damage/repair signaling pathways [15]. Histone acetylation could upregulate the expression of NBL2 that was associate in colorectal cancer cells, such as HCT116 cells [16]. Another study showed that histone acetylation modulated the transcriptional activities of several tumor suppressors and immune modulatory genes that related in colorectal cancer cells [17]. Also, a recent study showed that deletion of MOF in a mouse model of MLL-AF9 driven leukemogenesis reduced tumor burden and prolonged host survival [18]. According to these data, we concluded hMOF inhibitor may find application in the treatment of several types of cancer such as leukemia, colon cancer, NSCLC. Therefore, searching for selective inhibitor of hMOF not only can facilitate researching hMOF function in related diseases but also may contribute to make promising tools for the treatment of diseases mentioned above. Parallel to functional studies on HATs, researchers have aimed at developing small molecule inhibitors as chemical probes or potential therapeutic agents [19]. The current HAT inhibitors can be classified to three classes: bi-substrate, natural products, and novel small molecule inhibitors from virtual screening, high throughput screening or structure-based design [20]. The first bi-substrate inhibitor of HATs, H3-CoA-20 inhibitor was synthetized by Ronen Marmorstein's group at 2002 with an IC50 value of 300 nM on tGCN5 [21]. In addition to bi-substrate analogs, several natural products have been reported as HAT inhibitors. Anacardic acid from cashewnut shell liquid and garcinol from Garcinia indica fruit rind were isolated by Kundu's group, which has inhibition on p300 and PCAF, respectively [22,23]. Curcumin, a polyphenolic compound from curcuma longa rhizome, was shown to be a specific inhibitor of p300/CBP HAT activity with an IC50 value of 25 μM [24]. However, unlike natural products, a limited number of novel small molecules have been described as HATi. MB-3 has been discovered as a GCN5 inhibitor with an IC50 value of 100 μM [25]. Isothiazolones as inhibitors of PCAF and p300 showed antiproliferative properties against a panel of human colon and ovarian tumor cell lines [26]. A series of garcinol analogs (the LTK compounds) has been reported as p300-specific HAT inhibitors (IC50 values = 5–7 μM) but inactive for PCAF [27]. Quinoline derivatives have been described as HATi [[28], [29], [30]]. However, all these HATis reported have low selectivity and could not be made into drug due to their high toxicity and low-permeability.