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Acriflavine inhibits the epithelial-to-mesenchymal transition in vitro in liver and pancreatic cancer cells (part of study on HepG2)

ABSTRACT: Background: Epithelial-to-mesenchymal transition (EMT) is considered an important driving mechanism behind aggressive cancer phenotype. This was recently challenged by the finding that cells can metastasize without undergoing EMT. However, the same studies confirmed the important role of the EMT program in drug resistance. The EMT program is largely dependent on the cell’s microenvironment. Acriflavine (ACF) is a heteroaromatic dye with antibacterial and antiviral effects. Recently, ACF was suggested as anticancer agent for its topoisomerase inhibitor activity. ACF further blocks the hypoxia-inducible factor (HIF) pathway, an important driver of cancer aggressiveness. How ACF works in cancer is however unknown. Aim: Identification of the working mechanism, molecular pathways and signaling of ACF in EMT cancer cells. To this end, three in vitro models were developed of EMT induction (human pancreatic cancer cells stimulated with TGF-b1, human pancreatic cancer cells stimulated with CoCl2, drug resistance against sorafenib in human liver cancer cells). Only the third model - drug resistance against sorafenib in HepG2 cells - is discussed in this GEO submission.

ORGANISM(S): Homo sapiens

PROVIDER: GSE82110 | GEO | 2017/03/08

SECONDARY ACCESSION(S): PRJNA324072

REPOSITORIES: GEO

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Project description:The epithelial to mesenchymal transition (EMT) has been well recognized for many decades as an essential early step in the progression of primary tumors towards metastases. Widespread epigenetic reprogramming of DNA and histone modifications tightly regulates gene expression and cellular activity during carcinogenesis, and epigenetic therapy has been developed to design efficient strategies for cancer treatment. As the first oral agent approved for the clinical treatment of cancer, sorafenib has significant inhibitory effects on tumor growth and EMT. However, a detailed understanding of the underlying epigenetic mechanism remains elusive. In this manuscript, we performed a ChIP-Seq assay to evaluate the activity of sorafenib on the genome-wide profiling of histone modifications. We demonstrate that sorafenib largely reverses the changes in histone modifications that occur during EMT in A549 alveolar epithelial cells. Sorafenib also significantly reduces the coordinated epigenetic switching of critical EMT-associated genes in accordance with their expression levels. Furthermore, we show that sorafenib potentiates histone acetylation by regulating the expression levels of histone-modifying enzymes. Collectively, these findings provide the first evidence that sorafenib inhibits the EMT process through an epigenetic mechanism, which holds enormous promise for identifying novel epigenetic candidate diagnostic markers and drug targets for the treatment of human malignancies. To further explore the underlying epigenetic mechanisms of EMT regulation by sorafenib, we chose conventional markers of active euchromatin such as H3K9ac and H3K4me3, and contrasted their architecture with the repressive structures associated with H3K27me3 and H3K9me3. The profiling of these four selected histone modifications was performed using ChIP-seq on control, TGF-M-NM-21-treated and sorafenib-treated cells. We further performed pair-wise comparisons among the three treatment conditions to assess the changes in the histone modifications within specific genomic regions during EMT.

Project description:Hepatocellular carcinoma (HCC) is the second prominent cause of cancer-associated death worldwide. Usually, HCC is diagnosed in advanced stages, where sorafenib, a multiple target ty-rosine kinase inhibitor, is used as the first line of treatment. Unfortunately, resistance to sorafenib is usually encountered within six months of the treatment. Therefore, there is a critical need to identify the underlying reasons for drug resistance. In the present study, we investigated the proteomic and metabolomics alterations accompanying to sorafenib resistance in hepatocellular carcinoma Hep3B cells by employing ultra-high-performance liquid chromatography quadrupole time of flight mass spectrometry (UHPLC-QTOF-MS). The Bruker Human Metabolome Database (HMDB) library was used to identify the differentially abundant metabolites through MetaboScape 4.0 software (Bruker). For protein annotation and identification, the Uniprot proteome for Homo sapiens (Human) da-tabase was utilised through MaxQuant. The results revealed that 27 metabolites and 18 proteins were significantly dysregulated due to sorafenib resistance in Hep3B cells compared to the parental phenotype. D-alanine, L-proline, o-tyrosine, succinic acid and phosphatidylcholine (PC, 16:0/16:0) were among the significantly altered metabolites. Ubiquitin carboxyl-terminal hydrolase isozyme L1, mitochondrial superoxide dismutase, UDP-glucose-6-dehydrogenase, sorbitol dehydrogenase and calpain small subunit 1 were among the significantly altered proteins. The findings revealed that resistant Hep3B cells demonstrated significant alterations in amino acid and nucleotide met-abolic pathways, energy production pathways and other pathways related to cancer aggressive-ness, migration, proliferation, and drug-resistance. Joint pathway enrichment analysis unveiled unique pathways, including the antifolate resistance pathway and other important pathways that maintain cancer cells' survival, growth, and proliferation. Collectively, the results identified po-tential biomarkers for sorafenib-resistant HCC and gave insights into their role in chemotherapeutic drug resistance, cancer initiation, progression, and aggressiveness, which may contribute to better prognosis and chemotherapeutic outcomes.

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Acriflavine inhibits the epithelial-to-mesenchymal transition in vitro in liver and pancreatic cancer cells (part of study on HepG2)

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