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Targeted inhibition of LIFR enhances therapeutic efficacy of HDAC inhibitors in triple negative breast cancer

ABSTRACT: Here, we examined the therapeutic utility of EC359 in improving the therapeutic efficacy of HDACi in TNBC models. BT-549 cells were treated with vehicle (DMSO), EC359, HDACi(Vorinostat), EC359+HDACi and the RNA was isolated and utilized for RNA-seq analysis. Our results demonstrated that the beneficial effect of the EC359+HDACi involves regulation of multiple genes that involved in several pathways including apoptosis, metabolism and cell cycle.

ORGANISM(S): Homo sapiens

PROVIDER: GSE163249 | GEO | 2021/12/02

REPOSITORIES: GEO

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Project description:The identification of recurrent somatic mutations in genes encoding epigenetic enzymes, coupled with biochemical studies demonstrating aberrant recruitment of epigenetic enzymes such as histone deacetylases (HDACs) and histone methyltransferases (HMTs) to promoter regions through association with oncogenic fusion proteins such as PML-RARM-NM-1 and AML1-ETO has provided a strong rationale for the development compounds that target the epigenome for the treatment of cancer. HDAC inhibitors (HDACi) are potent inducers of tumor cell apoptosis but it remains unclear why tumor cells are selectively sensitive to HDACi-induced cell death. Herein we assessed the biological and molecular responses of normal and transformed cells to the FDA-approved HDACi vorinostat. Both HDACi selectively killed cells of diverse tissue origin that had been transformed through the serial introduction of different oncogenes. Time course microarray expression profiling revealed that normal and transformed cells transcriptionally responded to vorinostat treatment. Over 4200 genes responded differently to vorinostat in normal and transformed cells and gene ontology and pathway analyses identified a tumor-cell-selective pro-apoptotic gene-expression signature that consisted of BCL2 family genes. In particular, HDACi induced tumor cell-selective upregulation of the pro-apoptotic gene BMF and downregulation of the pro-survival gene BCL2A1 encoding BFL-1. Maintenance of BFL-1 levels in transformed cells through forced expression conferred vorinostat resistance indicating that specific and selective engagement of the intrinsic apoptosis pathways underlies the tumor cell-selective apoptotic activities of these agents. The ability of HDACi to affect the growth and survival of tumor cells whilst leaving normal cells relatively unharmed is fundamental to their successful clinical application. This study provides new insight into the transcriptional effects of HDACi in human donor-matched normal and transformed cells, and identifies molecules and pathways that could underpin the tumor-selective cytotoxic activity of these compounds. Whole genome expression profiling was performed for vorinostat-treated samples and control samples (DMSO vehicle control). Fourteen samples were included in this study. Each sample has three biological replicates, making forty-two arrays in total.

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Targeted inhibition of LIFR enhances therapeutic efficacy of HDAC inhibitors in triple negative breast cancer

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