Epigenetic silencing of triple negative breast cancer hallmarks by Withaferin A
Katarzyna Szarc Vel Szic1,2, Ken Declerck1, René A J Crans1,3
1Laboratory of Protein Chemistry, Proteomics and Epigenetic Signaling (PPES), Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium.
Abstract:
Triple negative breast cancer (TNBC) is characterized by poor prognosis and a DNA hypomethylation profile. Withaferin A (WA) is a plant derived steroidal lactone which holds promise as a therapeutic agent for treatment of breast cancer (BC). We determined genome-wide DNA methylation changes in weakly-metastatic and aggressive, metastatic BC cell lines, following 72h treatment to a sub-cytotoxic concentration of WA. In contrast to the DNA demethylating agent 5-aza-2'-deoxycytidine (DAC), WA treatment of MDA-MB-231 cells rather tackles an epigenetic cancer network through gene-specific DNA hypermethylation of tumor promoting genes including ADAM metallopeptidase domain 8 (ADAM8), urokinase-type plasminogen activator (PLAU), tumor necrosis factor (ligand) superfamily, member 12 (TNFSF12), and genes related to detoxification (glutathione S-transferase mu 1, GSTM1), or mitochondrial metabolism (malic enzyme 3, ME3). Gene expression and pathway enrichment analysis further reveals epigenetic suppression of multiple cancer hallmarks associated with cell cycle regulation, cell death, cancer cell metabolism, cell motility and metastasis. Remarkably, DNA hypermethylation of corresponding CpG sites in PLAU, ADAM8, TNSF12, GSTM1 and ME3 genes correlates with receptor tyrosine-protein kinase erbB-2 amplification (HER2)/estrogen receptor (ESR)/progesterone receptor (PR) status in primary BC tumors. Moreover, upon comparing differentially methylated WA responsive target genes with DNA methylation changes in different clinical subtypes of breast cancer patients in the cancer genome atlas (TCGA), we found that WA silences HER2/PR/ESR-dependent gene expression programs to suppress aggressive TNBC characteristics in favor of luminal BC hallmarks, with an improved therapeutic sensitivity. In this respect, WA may represent a novel and attractive phyto-pharmaceutical for TNBC treatment.
Insights
Withaferin A (WA) shows promise for treating triple negative breast cancer (TNBC). It induces gene-specific DNA hypermethylation, suppressing aggressive cancer traits and favoring less aggressive subtypes, suggesting a potential new phyto-pharmaceutical therapy.
Area of Science:
- Epigenetics
- Cancer Biology
- Pharmacology
Background:
- Triple negative breast cancer (TNBC) presents a poor prognosis and is linked to DNA hypomethylation.
- Withaferin A (WA), a plant-derived steroidal lactone, is a potential therapeutic agent for breast cancer (BC).
Purpose of the Study:
- To investigate the genome-wide DNA methylation changes induced by WA treatment in BC cell lines.
- To explore the potential of WA as a therapeutic agent for TNBC by analyzing its epigenetic effects.
Main Methods:
- Treatment of weakly-metastatic and aggressive BC cell lines with a sub-cytotoxic concentration of WA for 72 hours.
- Genome-wide DNA methylation profiling and gene expression analysis.
- Comparison of WA-induced methylation changes with clinical BC subtypes from The Cancer Genome Atlas (TCGA).
Main Results:
- WA treatment led to gene-specific DNA hypermethylation of tumor-promoting genes (e.g., ADAM8, PLAU, TNFSF12) and genes involved in detoxification and metabolism (GSTM1, ME3).
- Epigenetic suppression of cancer hallmarks including cell cycle regulation, metabolism, motility, and metastasis was observed.
- WA-induced hypermethylation correlated with HER2/ESR/PR status in primary tumors and silenced HER2/PR/ESR-dependent programs, shifting BC characteristics towards luminal subtypes.
Conclusions:
- WA acts on an epigenetic network, inducing gene-specific DNA hypermethylation rather than global demethylation.
- WA treatment suppresses aggressive TNBC characteristics and promotes luminal BC hallmarks, indicating potential therapeutic sensitivity.
- Withaferin A emerges as a promising phyto-pharmaceutical candidate for TNBC treatment.
Related Concept Videos
01:37Epigenetic Regulation
X-chromosome...
01:46Epigenetic Regulation
01:22MicroRNAs
01:22MicroRNAs
02:30Genomic Imprinting and Inheritance
The expression of some genes depends on which parent passed the gene to the offspring, through a phenomenon known as...
01:12Loss of Tumor Suppressor Gene Functions
When the tumor suppressor genes develop mutations or are lost, cells start growing out of control, leading to cancer. However, a single functional copy of the tumor suppressor gene is enough for the cells to maintain their normal functions and cell...