Novel SAHA analogues inhibit HDACs, induce apoptosis and modulate the expression of microRNAs in hepatocellular carcinoma

• Published in: Apoptosis (London) Vol. 21; no. 11; pp. 1249 - 1264
• Main Authors: Srinivas, Chatla, Swathi, V., Priyanka, C., Anjana Devi, T., Subba Reddy, B. V., Janaki Ramaiah, M., Bhadra, Utpal, Bhadra, Manika Pal
• Format: Journal Article
• Language: English
• Published: New York Springer US 01-11-2016; Springer Nature B.V
• Subjects: Apoptosis - drug effects; Biochemistry; Biomedical and Life Sciences; Biomedicine; Cancer Research; Carcinoma, Hepatocellular - drug therapy; Carcinoma, Hepatocellular - genetics; Carcinoma, Hepatocellular - metabolism; Carcinoma, Hepatocellular - physiopathology; Cell Biology; Cell Line, Tumor; Cell Proliferation - drug effects; Histone Deacetylase Inhibitors - chemistry; Histone Deacetylase Inhibitors - pharmacology; Histone Deacetylases - genetics; Histone Deacetylases - metabolism; Humans; Hydroxamic Acids - chemistry; Hydroxamic Acids - pharmacology; Liver Neoplasms - drug therapy; Liver Neoplasms - genetics; Liver Neoplasms - metabolism; Liver Neoplasms - physiopathology; MicroRNAs - genetics; MicroRNAs - metabolism; Molecular Structure; Oncology; Virology; Histones; SAHA; microRNA; Hepatocellular carcinoma; HDAC
• ISSN: 1360-8185; 1573-675X
• DOI: 10.1007/s10495-016-1278-6

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.