Inhibition of hTERT in pancreatic cancer cells by pristimerin involves suppression of epigenetic regulators of gene transcription

Deeb,Dorrah; Gao,Xiaohua; Liu,Yong Bo; Zhang,Yiguan; Shaw,Jiajiu; Valeriote,Frederick A.; Gautam,Subhash C.

doi:10.3892/or.2017.5400

Inhibition of hTERT in pancreatic cancer cells by pristimerin involves suppression of epigenetic regulators of gene transcription

Authors:
- Dorrah Deeb
- Xiaohua Gao
- Yong Bo Liu
- Yiguan Zhang
- Jiajiu Shaw
- Frederick A. Valeriote
- Subhash C. Gautam
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Affiliations: Departments of Surgery, Henry Ford Health System, Detroit, MI, USA, Drug Discovery Laboratories, Henry Ford Health System, Detroit, MI, USA
Published online on: January 23, 2017 https://doi.org/10.3892/or.2017.5400
Pages: 1914-1920

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Abstract

Previously we have shown that the inhibition of proliferation and induction of apoptosis in pancreatic ductal adenocarcinoma (PDA) cells by pristimerin (PM), a quinonemethide triterpenoid, was associated with the inhibition of human telomerase reverse transcriptase (hTERT) mRNA and hTERT protein. Herein we show that PM inhibits transcription factors and epigenetic processes that regulate hTERT expression. Treatment with PM inhibited transcription factors c-Myc, Sp1, NF-κB and kinases p-Akt and p-mTOR that regulate hTERT post-translationally. PM also downregulated DNA methyl transferases DNMT1 and DNMT3a and transcriptionally active chromatin markers, such as acetylated histone H3 (Lys9), acetylated histone H4, di-methyl H3 (Lys4) and tri-methyl H3 (Lys9). In addition, chromatin immunoprecipitation (ChIP) analysis showed decrease in c-Myc and Sp1 transcription factors, but not repressive factors CTCF, E2F or Mad1 in the regulatory region of the hTERT promoter after treatment with PM. PM also reduced acetylated histone 3 and 4 and methylated H3 at hTERT promoter. Collectively, these results indicated that PM downregulates hTERT/telomerase through the inhibition of the genetic and epigenetic regulators of hTERT gene expression.

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