Histone deacetylase inhibitors modulate miRNA and mRNA expression, block metaphase, and induce apoptosis in inflammatory breast cancer cells

Abstract

To develop new therapies for inflammatory breast cancer (IBC) we have compared the effects of two hydroxamic acid-based histone deacetylase (HDAC) inhibitors, CG-1521 and Trichostatin A (TSA) on the biology of two IBC cell lines: SUM149PT and SUM190PT. CG-1521 and TSA induce dose (0−10 µM) and time-dependent (0−96 h) increases in the proportion of cells undergoing cell cycle arrest and apoptosis in the presence or absence of 17β-estradiol. In SUM 149PT cells, both CG-1521 and TSA increase the levels of acetylated α-tubulin; however the morphological effects are different: CG-1521 blocks mitotic spindle formation and prevents abscission during cytokinesis while TSA results in an increase in cell size. In SUM190PT cells CG-1521 does not cause an increase in acetylated-α-tubulin and even though TSA significantly increases the levels of acetylated tubulin, neither inhibitor alters the morphology of the cells. Microarray analysis demonstrates that CG-1521 modulates the expression of 876 mRNAs and 63 miRNAs in SUM149PT cells, and 1227 mRNAs and 35 miRNAs in SUM190PT cells. Only 9% of the genes are commonly modulated in both cell lines, suggesting that CG-1521 and TSA target different biological processes in the two cell lines most likely though the inhibition of different HDACs in these cell lines. Gene ontology (GO) analysis reveals that CG-1521 affects the expression of mRNAs that encode proteins associated with the spindle assembly checkpoint, chromosome segregation, and microtubule-based processes in both cell lines and has cell-type specific effects on lipid biosynthesis, response to DNA damage, and cell death.

MicroRNA-31 Is a Transcriptional Target of Histone Deacetylase Inhibitors and a Regulator of Cellular Senescence

“…The exact mechanism of the inhibition of PcG proteins by HDACi is not known. HDACi can also differentially regulate expression of miRNAs in cancer cells (27)(28)(29)(30). For example, miR-125a, miR-125b, and miR-205 are known to be up-regulated by HDACi in breast cancer cells (31).…”

Identifying the impact of inflammatory breast cancer on survival: a retrospective multi-center cohort study

“…Applying new analysis strategies like highthroughput molecular analyses and next generation sequencing could help to better define the differences between IBC and other types of breast cancer. Moreover research should focus on the pattern of histone modifications in IBC and non-IBC as well as the role of alternative splicing [49][50][51]. Just the molecular analysis of tumor biology will offer the chance for new specific targeted therapy strategies.…”

RNAi and miRNA in Viral Infections and Cancers

“…Gains and losses of miRNA expression have been associated with cancer development and progression. However, the evidence that miRNAs directly participate in cancer development is limited (Chatterjee et al, 2013).…”

“…The region of miR-H2 in HSV is conserved and it is possible that this viral miRNA downregulate both viral ICP0 mRNA and a similar set of cellular transcripts (Leucci et al, 2010;Malterer et al, 2011). In apoptosis regulators include pro apoptotic factor (PUMA), which is a target of EBV miR-BART5 (Chatterjee et al, 2013). Suppression of PUMA by miR-BART5 may protect EBV infected cells from virus-induced apoptosis.…”