Epigenetic remodeling under oxidative stress: Mechanisms driving tumor metastasis

Abstract

Tumor metastasis is a multistep, inefficient process orchestrated by diverse signaling pathways. Compared to primary tumor cells, disseminated tumor cells inevitably encounter higher oxidative stress in foreign environments. The levels of reactive oxygen species (ROS) fluctuate dynamically during different metastatic stages, adding complexity to the regulation of metastatic progression. Numerous studies suggest that epigenetic remodeling, a key reversible mechanism of gene regulation, plays a critical role in responding to oxidative stress and controlling gene expression profiles that drive metastasis. Despite extensive research, a comprehensive understanding of how oxidative stress impacts metastasis through epigenetic modifications remains elusive, such as DNA methylation, histone modification, ncRNAs, and m⁶A modification. Epigenetic therapeutic strategies, such as DNMT inhibitors, HDAC inhibitors (HDACis), and miRNA mimics, have shown promise, yet challenges related to immunogenicity, specificity, and delivery also exist. Furthermore, due to limited understanding, some drugs targeting m⁶A modification have yet to be explored. In this review, we provided an overview of how oxidative stress influences tumor metastatic behavior, summarized the epigenetic mechanisms involved in these processes, and reviewed the latest advancements in epigenetic-targeted therapies, which may pave the way to develop novel strategy for preventing or treating tumor metastasis.