Epigenetic remodeling under oxidative stress: mechanisms driving tumor metastasis

This review is designed by Dr. Yunlong Lei(Biochemistry and Molecular Biology, and Molecular Medicine and Cancer Research Center, Chongqing Medical University), and written by B.S. Peilan Peng and PhD Siyuan Qin (State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University). Continuous oxidative stress is a hallmark of tumor biology, playing a pivotal role in all stages of metastasis. Generally, cancer cells exhibit markedly altered redox homeostasis, characterized by increased reactive oxygen species (ROS) production and enhanced expression of antioxidant genes. Peng and Qin reviewed the function of oxidative stress in the whole process of tumor metastasis, mainly including epithelial-mesenchymal transformation (EMT), the extracellular matrix (ECM) remodeling,  circulating tumor cells (CTCs) survival, and distal colonization.

Oxidative stress-induced regulation is complex and highly context-dependent due to the fluctuation of ROS levels among different metastasis stages. Epigenetic remodeling, as a reversible gene regulation strategy, is well-suited to respond to the shifting oxidative stress landscape, providing tumor cells with enhanced adaptability. Based on this, Peng and Qin further comprehensively summarized the epigenetic regulation mechanism of oxidative stress on tumor metastasis, from DNA methylation, histone modification, ncRNAs and m6A modification, respectively. ROS gradually remodel epigenetic patterns by recruiting epigenetic modifiers and regulating their activity, thus silencing or activating metastasis-related gene expression.

The team comprehensively summarized the progress of epigenetic drugs according to their acting mechanisms. Some natural oxidants/antioxidants have also been investigated in treating metastatic tumors, some of which effectively suppress metastasis through modulating epigenetic modification. Given the importance of ROS-induced epigenetic regulation on tumor metastasis, the therapeutic strategy of combining oxidative stress modulators and epigenetic drugs has shown certain advantages.

Meanwhile, several natural antioxidants have also been evaluated in treating metastatic tumors, some of which effectively suppress metastasis through modulating epigenetic modification. In addition, the therapeutic strategy of combining oxidative stress modulators and epigenetic drugs has also shown certain advantages.  The researchers summarized different therapeutic strategies against tumor metastasis, including single epigenetic drugs, oxidants/antioxidants with epigenetic regulation, and nano-drugs combining ROS-inducer and epigenetic modulators.

Based on a thorough understanding and summary of the mechanisms of ROS-modulated epigenetic regulations, their roles in tumor metastasis, and their targeting drugs, Peng and Qin also provided novel insights regarding future directions of research in this field. This comprehensive review is beneficial to optimize existing treatments and develop new strategies to combat metastasis.

See the article: 

Epigenetic remodeling under oxidative stress: mechanisms driving tumor metastasis

doi.org/10.1002/mog2.70000