Depletion of HDAC1, 7 and 8 by Histone Deacetylase Inhibition Confers Elimination of Pancreatic Cancer Stem Cells in Combination with Gemcitabine

Overview

Journal Sci Rep

Specialty Science

Date 2018 Jan 28

PMID 29374219

Citations 37

Authors

Mao-Hua Cai

Xiao-Gang Xu

Shi-Li Yan

Ze Sun

Yin Ying

Bai-Kui Wang

Yue-Xing Tu

Affiliations

Soon will be listed here.

Abstract

Trichostatin A (TSA) possess histone deacetylase (HDAC) inhibitory potential, can reverse the deactivation of tumor suppressor genes and inhibit tumor cell proliferation. We evaluated the effect of TSA on HDAC expression, tumor cell proliferation, and cancer stem cells (CSCs) activities in pancreatic ductal adenocarnoma (PDAC) cells. The PDAC cell lines MiaPaCa-2 and PANC-1 were distinctly sensitive to TSA, with enhanced apoptosis, compared to SAHA. TSA or SAHA inhibited vimentin, HDACs 1, 7 and 8, upregulated E-cadherin mRNA and protein levels in the PDAC cells, and time-dependently downregulated Oct-4, Sox-2, and Nanog, as well as inhibited PDAC tumorsphere formation. TSA also induces accumulation of acetylated histones, while increasing histone 3 lysine 4 or 9 dimethylation levels in PDAC cells and enhancing the epigenetic activity of SAHA. The anti-CSCs effect of TSA was like that obtained by silencing HDAC-1 or 7 using siRNA, and enhances Gemcitabine activity. Our study highlights the molecular targetability of HDACs 1, 7, and 8, confirm their PDAC-CSCs maintaining role, and demonstrate that compared to SAHA, TSA modulates the epigenetically- mediated oncogenic activity of PDAC-CSCs, and potentiate Gemcitabine therapeutic activity, making a case for further exploration of TSA activity alone or in combination with Gemcitabine in PDAC therapy.

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