Histone deacetylase 3 inhibits expression of PUMA in gastric cancer cells

Abstract

During cancer development, tumor suppressor genes were silenced by promoter methylation or histone deacetylation. Histone deacetylases (HDACs) are important to maintain histone deacetylation. HDAC inhibitors (HDACis) were thus proposed as a new therapeutic approach to cancer. The current study aims to understand the effect and molecular mechanisms of HDACis on gastric cancer cells. Trichostatin A (TSA) significantly inhibited the growth of gastric cancer cells by inducing apoptosis. Gene profiling results showed PUMA (p53 upregulated modulator of apoptosis) as one of 122 genes upregulated in TSA-treated gastric cancer cells. PUMA was downregulated in gastric cancer cell lines and primary gastric carcinoma tissues. Patients with low PUMA expression had significant decreases in overall survival (HR, 2.04; p = 0.047). Ectopic PUMA expression inhibited the growth of gastric cancer cells while PUMA depletion promoted cellular growth. The knockdown of HDAC3 but not other HDACs upregulated PUMA expression. HDAC3 could bind to PUMA promoter, which was abrogated after TSA treatment. In contrast to TSA and SB, HDAC3 siRNA failed to upregulate p53 expression but promoted the interaction of p53 with PUMA promoter. In summary, proapoptotic PUMA was downregulated in gastric cancer and its mRNA expression level is a valuable prognosis factor for gastric cancer. HDAC3 is important to downregulate PUMA expression in gastric cancer and HDACis, like TSA, promoted PUMA expression through stabilizing p53 in addition to HDAC3 inhibition. In combination with chemotherapy, targeting HDAC3 might be a promising strategy to induce apoptosis of gastric cancer cells.

HDACs and HDAC Inhibitors in Cancer Development and Therapy

“…Inhibition of HDAC8 by methylselenopyruvate (MSP), a competitive inhibitor of HDAC8, was sufficient to activate BMF transcription and promote BMF-mediated apoptosis in colon cancer cells (Kang et al 2014). HDAC3 downregulates PUMA expression in gastric cancer cells and HDACi, like TSA, promotes PUMA expression through enhancing the binding of p53 to the PUMA promoter (Feng et al 2013). TSA treatment can also effectively overcome resistance to DNA damage–induced cell death by reactivating PUMA expression in renal cell carcinoma cells (Zhou et al 2014).…”

Histone deacetylase inhibitors and cell death

“…However, following HDAC inhibition, acetylation of p53 has been reported in several tumor systems, which has been related to p53 stabilization, cell cycle arrest, and apoptosis [132-134]. More recently, studies have shown that HDAC inhibitor TSA prompts PUMA expression to induce apoptosis in gastric cancer cells via two independent ways: p53 stabilization and p53 interaction with the PUMA promoter through the inhibition of HDAC3 [135]. …”

YY1-MIR372-SQSTM1 regulatory axis in autophagy

“…45 Briefly, cells were first fixed with 4% formaldehyde. Cells were then lysed and chromatin was harvested and fragmented using enzyme digestion.…”