Chemoprevention of Skin Cancer: The Potential Role of Epigenetics and Skin Cancer Stem Cells

Abstract

Melanoma, an aggressive form of skin cancer, is influenced by UVB radiation, leading to inflammation, metastasis, and compromised treatment response. The incidence of melanoma is projected to rise continuously in the coming years. Despite advancements in therapeutic approaches for managing melanoma metastasis, the survival rates for patients with metastatic melanoma remain disappointingly low. Cancer stem cells (CSCs), a specific subset of cells, play a critical role in tumor recurrence and differentiation. CSCs are known to be maintained through epigenetic modifications involving microRNAs and DNA methylation. Plant polyphenols have shown significant potential in cancer prevention and treatment, with miRNAs and DNA methylation acting as novel effectors in their biological activities. Recent research has revealed the ability of a novel bacterium (SV-53) to enhance the polyphenolic content of blueberry juice through biotransformation. Polyphenol-enriched blueberry Preparation (PEBP) and an Oligomeric Mixture of Polyphenols (OMP) have demonstrated chemopreventative properties on breast, skin, and lung cancer stem cells. Based on these findings, our hypothesis suggests that the small bioactive polyphenolic oligomers present in PEBP and OMP can induce epigenetic modifications in global regulators. This epigenetic modulation is expected to trigger a systemic protective response, reducing inflammation-induced carcinogenesis and preventing photodamage caused by UVB radiation. A series of studies were conducted to test the hypothesis. Firstly, we investigated the mechanisms through which PEBP and OMPs inhibit melanoma cancer stem cell proliferation and differentiation. This involved studying the regulation of gene expression of miR-200c and miR-210, as well as their targets in epithelial-mesenchymal transition (EMT)-related pathways, using in vitro and ex vivo experiments (Article 1). Next, we focused on exploring the ability of OMP treatment to suppress melanoma cancer progression through EMT-mediated signaling and epigenome regulation. Specifically, we targeted miRNAs and the DNA methylome in an in vivo study (Article 2). Lastly, we examined the potential of topically applying PEBP and OMP to reduce inflammation in UVB-affected tissues, as these compounds possess the potential to modulate these intricate processes (Article 3).

The insights gained from understanding the impact of PEBP and OMP on epigenetic changes can pave the way for novel therapeutic approaches in managing melanoma and targeted strategies to mitigate photodamage caused by UVB radiation. Furthermore, this study will contribute novel evidence-based insights for supportive care and establish a foundation for the preclinical evaluation of polyphenol-enriched preparations to enhance the efficacy of chemotherapy and improve the therapeutic index.