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The effect of DZNeP-exposure on activation of hepatic stellate cells analyzed by RNA-sequencing.

ABSTRACT: DZNeP is the inhibitor of Ezh2 and paly negative roles on activation of hepatic stellate cells. We used RNA sequencing to identify the effective genes of DZNeP in rat HSCs. The primary rat HSCs was isolated and purified from SD rats, and cultured in DMEM culture medium with 20% FBS for 24 hours. Then the rat HSCs was administrated with DZNeP at 1μM concentration, or with similar volume of DMSO as negative control. 48 hour later, the cells were harvested and cell lysis was subjected to RNA-sequencing. This study identified that DZNeP regulated HSC activation through upregulating the expression of many key anti-fibrotic factors including Tgfβ signaling inhibitor: Bambi; cell cycle inhibitors: p21, Gadd45s; and immunomodulatory cytokine IL10.

ORGANISM(S): Rattus norvegicus

PROVIDER: GSE121736 | GEO | 2020/09/30

REPOSITORIES: GEO

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Project description:The 3-Deazaneplanocin A (DZNep), one of S-adenosylhomocysteine (AdoHcy) hydrolase inhibitors, has shown antitumor activities in a broad range of solid tumors and acute myeloid leukemia. Here, we examined its effects on multiple myeloma (MM) cells and found that, at 500 nM, it potently inhibited growth and induced apoptosis in 2 of 8 MM cell lines. RNA from un-treated and DZNep treated cells was profiled by Affymetrix HG-U133 Plus 2.0 microarray and genes with a significant change in gene expression were determined by significance analysis of microarray (SAM) testing. ALOX5 was the most down-regulated gene (5.8-fold) in sensitive cells and was expressed at low level in resistant cells. The results were corroborated by quantitative RT-PCR. Western-blot analysis indicated ALOX5 was highly expressed only in sensitive cell line H929 and greatly decreased upon DZNep treatment. Ectopic expression of ALOX5 reduced sensitivity to DZNep in H929 cells. Furthermore, down-regulation of ALOX5 by RNA interference could also induce apoptosis in H929. Gene expression analysis on MM patient dataset indicated ALOX5 expression was significantly higher in MM patients compared to normal plasma cells. We also found that Bcl-2 was overexpressed in DZNep insensitive cells, and cotreatment with DZNep and ABT-737, a Bcl-2 family inhibitor, synergistically inhibited growth and induced apoptosis of DZNep insensitive MM cells. Taken together, this study shows one of mechanisms of the DZNep efficacy on MM correlates with its ability to down-regulate the ALOX5 levels. In addition, DZNep insensitivity might be associated with overexpression of Bcl-2, and the combination of ABT-737 and DZNep could synergistically induced apoptosis. These results suggest that DZNep may be exploited therapeutically for a subset of MM. Cells were treated with 0.5 μmol/L DZNep for 48 h. Total RNA was extracted by using the Qiagen RNeasy Mini kit (Germany). Gene expression was performed using the GeneChip® Human Genome U133A Array (Affymetrix) following the manufacturer’s instructions. Data analysis was performed using GeneSpring software from Agilent Technologies.

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The effect of DZNeP-exposure on activation of hepatic stellate cells analyzed by RNA-sequencing.

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