title: Novel SAHA analogues inhibit HDACs, induce apoptosis and modulate the expression of microRNAs in hepatocellular carcinoma.
abstract: In eukaryotes, transcriptional regulation occurs via chromatin remodeling, mainly through post translational modifications of histones that package DNA into structural units. Histone deacetylases (HDACs) are enzymes that play important role in various biological processes by repressing gene expression. Suberoylanilide hydroxamic acid (SAHA) is a known HDAC inhibitor that showed significant anti cancer activity by relieving gene silencing against hematologic and solid tumors. We have designed and synthesized a series of SAHA analogs C1-C4 and performed biological studies to elucidate its anti-cancer effects. It is observed that SAHA analogs significantly inhibited cell proliferation and induced apoptosis in hepatocellular carcinoma (HCC) cell lines HepG2 and SK-HEP-1. These analogs also showed non-toxic activity towards primary human hepatocytes, which describes its tumor specificity. SAHA analogs exhibited strong HDAC inhibition, which is 2-3 fold higher compared to SAHA. Moreover, these molecules induced hyper acetylation of histone H3 at various positions on the lysine residue. Further, it is observed that SAHA analogs are strong inducers of apoptosis, as they regulated the expression of various proteins involved in both extrinsic and intrinsic pathways. Interestingly, SAHA analogs induced upregulation of tumor suppressor miRNAs by activating its biogenesis pathway. Further, it is confirmed by microRNA (miRNA) prediction tools that these miRNAs are capable of targeting various anti-apoptotic genes. Based on these findings we conclude that SAHA analogs could be strong HDAC inhibitors with promising apoptosis inducing nature in HCC.
authors: Centre for Chemical Biology, CSIR-Indian Institute of Chemical Technology, Uppal Road, Hyderabad, 500007, India.
authors: Chatla
authors: C
authors: Srinivas
authors: Centre for Chemical Biology, CSIR-Indian Institute of Chemical Technology, Uppal Road, Hyderabad, 500007, India.|Centre for Semiochemicals, CSIR-Indian Institute of Chemical Technology, Hyderabad, India.
authors: V
authors: V
authors: Swathi
authors: Centre for Chemical Biology, CSIR-Indian Institute of Chemical Technology, Uppal Road, Hyderabad, 500007, India.
authors: C
authors: C
authors: Priyanka
authors: Centre for Chemical Biology, CSIR-Indian Institute of Chemical Technology, Uppal Road, Hyderabad, 500007, India.
authors: T
authors: T
authors: Anjana Devi
authors: Centre for Semiochemicals, CSIR-Indian Institute of Chemical Technology, Hyderabad, India.
authors: B V
authors: BV
authors: Subba Reddy
authors: School of Chemical and Biotechnology, SASTRA University, Thanjavur, India.
authors: M
authors: M
authors: Janaki Ramaiah
authors: Functional Genomics and Gene Silencing Group, CSIR-Centre for Cellular and Molecular Biology, Hyderabad, India.
authors: Utpal
authors: U
authors: Bhadra
authors: Centre for Chemical Biology, CSIR-Indian Institute of Chemical Technology, Uppal Road, Hyderabad, 500007, India. manika@iict.res.in.
authors: Manika Pal
authors: MP
authors: Bhadra
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D056572:Histone Deacetylase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000737:chemistry / Q000494:pharmacology*; D008113:Liver Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D015394:Molecular Structure; D000077337:Vorinostat
chemical_list: D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D035683:MicroRNAs; D000077337:Vorinostat; D006655:Histone Deacetylases
keywords: HDAC; Hepatocellular carcinoma; Histones; SAHA; microRNA