A novel benzamine lead compound of histone deacetylase inhibitor ZINC24469384 can suppresses HepG2 cells proliferation by upregulating NR1H4

Abstract

Histone deacetylases (HDACs) can enzymatically transferred acetyl functional group from protein or lysine residues of histone, so they can regulate the expression of lots of genes. Now HDACs are used as drug targets and many HDAC inhibitors (HDACis) were approved for cancer therapy or in clinical trials. However, the physiological mechanisms and regulatory processes of HDACi anti-cancer effects are largely unexplored and uncompleted. Here we use the virtual screening workflow obtained 25 hit compounds and ZINC24469384 can significantly inhibit HDAC activity while arrest cell cycle at G1/S phase and significantly induced HepG2 cell apoptosis, time-course RNA-seq demonstrate that HepG2 cells transcriptionally respond to ZINC24469384. Pathway analysis of DEGs and DASGs reveal that NR1H4 may play an important role in ZINC24469384-induced anti-proliferation effect and is dramatically alleviated by down-regulating the SOCS2 expression and promoting STAT3 phosphorylation in knockdown NR1H4 HepG2 cells. Analysis based on TCGA database indicated that NR1H4 and SOCS2 were downregulated in liver cancer, this suggest NR1H4 and SOCS2 may play an important role in tumorigenesis. These results indicated that ZINC24469384 is a novel benzamine lead compound of HDACi and provides a novel mechanism for HDACi to inhibit cancer.

HDAC Inhibitor, CG-745, Enhances the Anti-Cancer Effect of Anti-PD-1 Immune Checkpoint Inhibitor by Modulation of the Immune Microenvironment

“…Histone deacetylase inhibitors (HDACis) are potent epigenetic modulators that have various therapeutic potential and have pleiotropic effects at the cellular and systemic levels [25]. While HDACis in anti-cancer therapy are commonly known as apoptosis inducers through anti-cancer gene expression and cell cycle arrest, recent studies have shown anti-tumor efficacy of HDACis in certain cancer types [26][27][28][29]. CG-745 is a HDAC inhibitor, and it has been reported as a potent anti-cancer agent in cholangiocarcinoma, pancreatic cancer, prostate cancer, and non-small cell lung cancer [30][31][32][33].…”

Down-regulation of solute carrier family 10 member 1 is associated with early recurrence and poorer prognosis of hepatocellular carcinoma

“…An analysis based on the TCGA dataset indicated that NR1H4 was downregulated in liver cancer. This suggests that NR1H4 may play an important role in tumorigenesis [39]. If bile acid levels increase, FXR activates the expression of SHP and then SHP inhibits transcription of NTCP [40].…”

Discovery of novel class of histone deacetylase inhibitors as potential anticancer agents

“…This new class of HDAC inhibitors possesses an imidazopyridine moiety, which, to the best of our knowledge, has not been reported before. The inhibition of various HDACs by these compounds as well as their effects on acetylated histones, pro-apoptotic and antiapoptotic markers, cell cycle and anti-proliferative activity in the MCF7 breast cancer cell line were investigated [14][15][16] and are reported herein.…”