Epigenetic Regulation of Wnt Signaling in Cancer
Summary
The Wnt signalling network is a central regulator of cellular proliferation, differentiation and tissue homeostasis. In cancer, aberrant activation of canonical and non-canonical branches of Wnt signalling drives tumour growth, invasion and stem cell-like traits. Emerging evidence has shown that epigenetic modifications profoundly influence Wnt pathway activity without altering DNA sequence. DNA methylation of promoter CpG islands, histone modifications and non-coding RNAs converge on key components of the Wnt cascade, including ligand antagonists, intracellular scaffolds and transcriptional cofactors. Such alterations can silence tumour suppressors, deregulate β-catenin turnover and bias signalling towards oncogenic programmes. The reversible nature of many epigenetic marks has sparked interest in demethylating agents and histone deacetylase inhibitors as adjuvants to restore normal Wnt control. Moreover, epigenetic signatures of Wnt regulators have shown promise as prognostic biomarkers across diverse malignancies. Collectively, these findings underscore the global significance of epigenetic control in sculpting Wnt signalling outputs during cancer development and highlight novel avenues for targeted therapy and precision medicine.
Research from Nature Portfolio
Recent studies have unveiled critical roles for epigenetic silencing of DACT family antagonists in solid tumours. In type I epithelial ovarian cancer, restored expression of DACT1 was shown to attenuate β-catenin accumulation, diminish Dishevelled levels and re-sensitise cells to platinum-based chemotherapy through enhancement of autophagy. Tumours with low DACT1 expression exhibited more aggressive growth and chemoresistance, emphasising a therapeutic window for epigenetic reactivation. In breast carcinoma, frequent hypermethylation of the DACT2 promoter correlated with increased tumour size and poorer outcomes; re-expression of DACT2 suppressed Wnt-driven proliferation, induced G1/S cell cycle arrest and reduced xenograft growth. These insights identify DACT methylation as a conserved mechanism by which cancer cells bypass Wnt inhibition and reinforce the potential of targeted epigenetic therapies to reinstate tumour-suppressive networks.
Epigenetic Regulation of Wnt Signaling in Cancer publication trend
The graph below shows the total number of articles in epigenetic regulation of wnt signaling in cancer across all publications each year (not limited to Nature Index journals).
Technical terms
Epigenetics: Heritable changes in gene expression that do not involve alteration of the DNA sequence.
Wnt signalling: A complex network of proteins that regulate cell fate, proliferation and movement.
DNA methylation: Addition of methyl groups to cytosine bases in CpG dinucleotides, often leading to gene silencing.
Histone modification: Post-translational changes to histone proteins that influence chromatin structure and gene transcription.
CpG island: Regions rich in cytosine-guanine dinucleotides, commonly located near gene promoters.
Tumour suppressor: A gene that protects a cell from one step on the path to cancer and whose loss promotes tumourigenesis.
β-catenin: A central mediator of canonical Wnt signalling that regulates transcription of target genes.
Demethylating agents: Drugs that inhibit DNA methyltransferases to reverse abnormal DNA methylation and restore gene expression.
References
- DACT1 Overexpression in type I ovarian cancer inhibits malignant expansion and cis-platinum resistance by modulating canonical Wnt signalling and autophagy. Scientific Reports (2017).
- Methylation of DACT2 promotes breast cancer development by activating Wnt signaling. Scientific Reports (2017).
- Aberrant methylation of DACT1 and DACT2 are associated with tumor progression and poor prognosis in esophageal squamous cell carcinoma. Journal of Biomedical Science (2017).
- The new 6q27 tumor suppressor DACT2, frequently silenced by CpG methylation, sensitizes nasopharyngeal cancer cells to paclitaxel and 5-FU toxicity via β-catenin/Cdc25c signaling and G2/M arrest. Clinical Epigenetics (2018).
- Epigenetic regulation of the Wnt signaling inhibitor DACT2 in human hepatocellular carcinoma. Epigenetics (2013).
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