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  • Pharmacological G a inhibition resulted


    Pharmacological G9a inhibition resulted in significant reduction of viable BTC cells in a concentration- and cell line–dependent manner. Interestingly, we found a significant correlation between BIX01294-IC50 and UNC0642-IC50 values in our BTC cell model—both inhibitors competitively inhibit H3K9 substrate binding [20], [21]—whereas we found no correlation of BRD4770-IC50 (a S-adenosylmethionine [SAM, methyl donor] mimic [20]) with neither BIX01294-IC50, nor UNC0642-IC50. Importantly, by using different BTC cell lines and G9a inhibitors, the observed viability reduction is rather a result of actual G9a inhibition than a substance- or cell line–specific effect. However, future studies should investigate potential side and off-target effects of these substances in an appropriate BTC in vivo model.
    Supplementary data The following are the Supplementary data to this article.
    Author contributions
    Introduction Histone 3 lysine 4 methylation (H3K4me) plays a key role in the regulation of various cellular processes like replication, DNA damage response, BD 1047 dihydrobromide progression and transcriptional regulation of genes (Bhaumik et al., 2007; Shilatifard, 2006). In general, H3K4me is associated with efficient transcription of genes through recruitment of transcription factors in the promoter region (Kouzarides, 2007). It was evident from previous studies that the deregulation of H3K4me mark is involved in various human pathological diseases including tumors (Varier & Timmers, 2011). Histone methyltransferases (HMTs) are also called as lysine methyltransferases (KMTs), enzymes that add a methyl group to histone proteins using S-adenosyl methionine as a co-factor. The unique feature of KMTs is presence of SET domain, which possesses HMTase activity (Qian & Zhou, 2006). Set 1 was the BD 1047 dihydrobromide first HMT to be identified in yeast as a protein associated with a macromolecular complex known as COMPASS (complex of proteins associated with Set 1) and is responsible for all -mono, −di and –tri methylation of the H3K4 residue (Roguev et al., 2001). Although there are seven Set 1 related proteins viz.; SET1A, SET1B, MLL1, MLL2, MLL3, MLL4, and MLL5 in mammals that form a complex with COMPASS (Smith & Shilatifard, 2010). Further, these proteins are classified into three classes based on the specific components present within each class: SET1A and SET1B contain WDR82 and CXXC1 components, MLL1/2 contains Menin and MLL3/4 contains PTIP, PA-1, NCOA6, and UTX, which are important for their methylation activity (Mohan et al., 2011). MLL5 is a unique member of the KMT2 gene family lacking intrinsic methyltransferase activity (Rao & Dou, 2015). The roles of COMPASS family of HMTs are well studied in certain human cancers. For example, translocations of MLL genes are characteristic features of leukemia (Hess, 2004). In addition, they are also altered in various solid tumors like prostate (Bianco-Miotto et al., 2010), colorectal (Choi et al., 2014), breast (Salz et al., 2015), and gastric carcinomas (Choi et al., 2014). Their role as a prognostic indicator has been explored in lymphomas (Ye et al., 2015), pancreatic (Dawkins et al., 2016), and gastric cancers (Li et al., 2014). Notwithstanding, the knowledge of KMT2 family of HMTs is lacking in renal cell carcinoma (RCC). RCC represents 2% of all adult malignancies and 85% of all malignant kidney tumors (Kabaria et al., 2016). Of various histological subtypes, clear cell renal cell carcinoma (ccRCC) is the most common type followed by papillary and chromophobe RCC (Cairns, 2011). The early diagnosis of RCC is difficult because of the asymptomatic nature of the disease. Therefore, most of the cases are detected incidentally on radiological examinations, of which, one-third of the patients present with metastasis at the time of diagnosis, which decreases the overall survival rate to less than 20% for metastatic disease (Brugarolas, 2007). Surgery is the gold standard treatment of RCC but in case of metastasis, the prognosis is very poor and patients need systemic therapies, which are having low response rate (Hsieh et al., 2017). Therefore, there is an urgent need to develop any molecular signature for the detection of ccRCC metastasis.