Histone lysine methyltransferase SUV39H1 is a potent target for epigenetic therapy of hepatocellular carcinoma

Abstract

Histone H3 lysine 9 trimethylation (H3K9me3) is associated with transcriptional repression and regulated by histone lysine methyltransferases such as SUV39H1 and ESET. However, the functional roles of these enzymes in hepatocellular carcinoma (HCC) remain uncertain. In this study, we conducted loss-of-function assays for HCC cells. SUV39H1 knockdown but not ESET knockdown reduced H3K9me3 levels and impaired HCC cell growth and sphere formation. The pharmacological inhibition of SUV39H1 by chaetocin resulted in cell growth inhibition and inducing cellular apoptosis in culture and xenograft subcutaneous tumors. Real-time polymerase chain reaction analysis indicated high levels of SUV39H1 expression in 24 of 42 (57.1%) HCC surgical samples compared with corresponding nontumor tissues. Immunohistochemistry identified high levels of H3K9me3 and ESET proteins in 23 (54.8%) and 29 (69.0%) tumor tissues, respectively. However, these proteins' expressions were only observed in biliary epithelial cells and periportal hepatocytes of nontumor tissues. Expression levels of SUV39H1 but not those of ESET were significantly correlated with H3K9me3 levels. The cumulative HCC recurrence rate was significantly higher for patients with elevated SUV39H1 expression and H3K9me3 levels. In conclusion, our data indicate that elevated SUV39H1 expression and high levels of H3K9me3 have important roles in HCC development and progression. Therefore, the pharmacological inhibition of SUV39H1 may be a promising therapeutic approach for HCC treatment.Epigenetic mechanisms, including DNA methylation, histone modification and noncoding RNAs, are closely associated with transcriptional regulation in eukaryotic cells.

A functional single nucleotide polymorphism of SET8 is prognostic for breast cancer

“…For example, the expression level of histone lysine methyltransferase EZH2 which mainly catalyze H3K27me3 is higher in the breast cancer, prostate cancer and bladder cancer, and has been used as a prognostic marker in breast cancer and metastatic prostate cancer [34, 35]. Elevated expression of Suv39h1, another histone methyltransferase which can catalyze H3K9me2, has been found to associate with higher incidence of hepatocellular carcinoma recurrence [36]. As recently more and more research groups devote to explore molecule targeting inhibitors of histone methyltransferase, such as EZH2- H3K27 inhibitor EPZ – 6438 [37] and DOT1L- H3K79 methylation inhibitors EPZ– 5676 [38], it has become a promising target for anti-tumor therapy [39, 40].…”

Inflammatory cytokine IL6 cooperates with CUDR to aggravate hepatocyte-like stem cells malignant transformation through NF-κB signaling

“…SUV39H1 knockdown reduced H3K9me3 levels and impaired HCC cell growth and sphere formation. Elevated SUV39H1 expression and high levels of H3K9me3 have important roles in HCC development and progression3536. The sustained expression of SUV39H1 delays the repair of constitutive heterochromatin (HC) DNA and reduces clonogenic survival after ionizing irradiation37.…”

Low expression of endothelin receptor B (EDNRB) is related to H3K9me3 binding with the EDNRB promoter region and is associated with the clinical T tumor stage in salivary adenoid cystic carcinoma

“…On the basis of our preliminary experiments and other previous studies, we chose four concentrations: 10 nmol/L, 20 nmol/L, 40 nmol/L, and 80 nmol/L for the study. 19,20 After treatment with 10 nmol/L, 20 nmol/L, 40 nmol/L, or 80 nmol/L chaetocin for 48 hours, total mRNA were extracted from SACC-83 and SACC-LM cells and reverse transcribed into complementary deoxyribonucleic acid (cDNA). The qRT-PCR results showed that when the drug concentration was 80 nM, the mRNA level of the EDNRB significantly increased (Figures 4B and 4C).…”