Effect of Valproic Acid on the Class I Histone Deacetylase 1, 2 and 3, Tumor Suppressor Genes p21WAF1/CIP1 and p53, and Intrinsic Mitochondrial Apoptotic Pathway, Pro- (Bax, Bak, and Bim) and anti- (Bcl-2, Bcl-xL, and Mcl-1) Apoptotic Genes Expression, Cell Viability, and Apoptosis Induction in Hepatocellular Carcinoma HepG2 Cell Line

Abstract

Backgrounds: Hepatocellular carcinoma (HCC), Primary liver cancer, is the fifth most common cancer in men. Histone deacetylation causes chromatin condensation resulting in gene silencing and tumorigenesis. These enzymes have become a novel target for the treatment of cancer. Histone deacetylase inhibitors (HDACIs) can reactivate tumor suppressor genes (TSGs) by inhibition of histone deacetylases (HDACs) activity leads to apoptosis induction in cancer cells. Further, these compounds can induce apoptosis through the intrinsic/mitochondrial pathway. Previously, we reported the effect of valproic acid (VPA) and trichostatin A (TSA) on TSGs p21 WAF1/CIP1 (p21), p27 Kip1 (p27), and p57 Kip2 (P57) and also HDAC1 in colon cancer. The present study was designed to investigate the effect of VPA on the class I histone deacetylase (HDAC) 1, 2 and 3, TSGs p21and p53, and intrinsic mitochondrial pathway, pro-(Bax, Bak, and Bim) and anti-(Bcl-2, Bcl-xL, and Mcl-1) apoptotic genes, viability, and apoptosis in HCC HepG2 cell line. Materials and Methods: The HepG2 cells were cultured and treated with VPA. To determine viability, apoptosis, and the relative expression level of the mentioned genes, MTT assay, cell apoptosis assay, and qRT-PCR were done respectively. Results: VPA downregulated class I histone deacetylase (HDAC) 1, 2, and 3, Bcl-2, Bcl-xL, and Mcl-1 and upregulated p21, p53, Bax, Bak, and Bim resulting in apoptosis induction. Conclusion: VPA can induce apoptosis via activation of the intrinsic mitochondrial apoptotic pathway and also epigenetic reactivation of p21 and p53 through inhibition of class I HDAC 1, 2 and 3, activity.

Resistance Mechanisms in Pediatric B-Cell Acute Lymphoblastic Leukemia

“…This is associated with decreased venetoclax binding, increased anti-apoptotic family members associated with BCL-2, changes in the microenvironment, and malfunction of the TP53 pathway [ 103 ]. In the context of chronic venetoclax exposure, it increases MCL1 and BCL-XL expression, both of which have antiapoptotic properties [ 104 ], leading to acquired resistance [ 103 ]. This suggests that drugs may lead to resistance by activating already existent cellular pathways.…”

Preclinical Evaluation of Dimethyl Itaconate Against Hepatocellular Carcinoma via Activation of the e/iNOS-Mediated NF-κB–Dependent Apoptotic Pathway

“…The Bcl-2 family regulates the mitochondrial pathway, which releases both pro-apoptotic (BAX and BAD) and antiapoptotic (Bcl-2 and Bcl-xl) proteins. All of these apoptogenic signals are thought to cause the release of CytC from mitochondria, which then connect with procaspase 9 and APAF1 to create an apoptosome (Rang et al, 2011;Sanaei and Kavoosi, 2021). In the presence of caspase-3 and caspase-9, this apoptosome causes apoptosis.…”

Anti-proliferative and Apoptotic Effects of Valproic Acid on HeLa Cells

“…Some studies support the role of VPA treatment in the upregulation of p53 and p21. For instance, Sanaei and Kavoosi demonstrated that VPA could downregulate HDAC 1, 2, and 3, and anti-apoptotic genes, including Bcl-2, Bcl-xL, and Mcl-1, and upregulate pro-apoptotic genes, including Bax, Bak, Bim, p53, and p21 in HepG2 cell line, suggesting that VPA induces intrinsic pathway of apoptosis (35). Mechanistically, VPA increases the pro-apoptotic activity of p53 at the mitochondrial membrane by stabilizing its acetyl modifica- tion at lysine 120 (36).…”