Transcriptional hallmarks of cancer cell lines reveal an emerging role of branched chain amino acid catabolism

Ieva Antanavičiūtė,Gintarė Milašiūtė,Sergio Bordel,Vytenis Arvydas Skeberdis,Valeryia Mikalayeva,Ieva Ceslevičienė

doi:10.1038/s41598-017-08329-8

Abstract

A comparative analysis between cancer cell lines and healthy dividing cells was performed using data (289 microarrays and 50 RNA-seq samples) from 100 different cancer cell lines and 6 types of healthy stem cells. The analysis revealed two large-scale transcriptional events that characterize cancer cell lines. The first event was a large-scale up-regulation pattern associated to epithelial-mesenchymal transition, putatively driven by the interplay of the SP1 transcription factor and the canonical Wnt signaling pathway; the second event was the failure to overexpress a diverse set of genes coding membrane and extracellular proteins. This failure is putatively caused by a lack of activity of the AP-1 complex. It was also shown that the epithelial-mesenchymal transition was associated with the up-regulation of 5 enzymes involved in the degradation of branched chain amino acids. The suitability of silencing one of this enzymes (branched chain amino acid transaminase 2; BCAT2) with therapeutic effects was tested experimentally on the breast cancer cell line MCF-7 and primary cell culture of breast tumor (BCC), leading to lower cell proliferation. The silencing of BCAT2 did not have any significant effect on ASM and MCF10A cells, which were used as models of healthy dividing cells.

Highlights

Side effects are among the main problems related to chemotherapy
The first identified event is associated with the phenomenon of epithelial-mesenchymal transition and appears to be more intense in cancer cell lines and healthy mesenchymal stem cells compared to epithelial stem cells
Based on gene enrichment analysis, the transcription factors SP1, LEF1, and FOXO4 have been identified as putative drivers of this large-scale transcriptional pattern

Summary

Introduction

Side effects are among the main problems related to chemotherapy. Most of the drugs used in chemotherapy target DNA replication or key regulators of the cell cycle[1], which has a negative impact on malignant cells and on healthy proliferating cells (stem cells and progenitors), leading to stem cell depletion and impaired renewal and function of healthy tissues[2]. The development of high throughput omics technologies such as cDNA microarrays and more recently, RNA-sequencing, has led to the accumulation of large datasets that constitute rich sources of information allowing us to identify systematic differences that characterize cancer cells These transcriptional differences are expected to provide keys for the design of therapies targeting cancer cells without damaging healthy dividing cells and to minimize the secondary effects associated with stem cell depletion caused by chemotherapy. The TP53 tumor suppressor is the most frequently mutated gene, but it is still far from being present in all sequenced cancers Despite this large heterogeneity in the mutations that trigger malignant transformations, cancer has been characterized in terms of a small set of hallmarks described by Hannahan and Weinberg[9]. Healthy proliferating cells, with the aim of identifying transcriptional hallmarks present in cancer cell lines and absent in healthy cells

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