Regulations of m6A and other RNA modifications and their roles in cancer

Cancer, a disease with global implications, is closely linked to dysregulated gene expression, which is influenced by both genetic mutations and epigenetic changes, including RNA modifications. A full review published in Frontiers of medicine reveals the important role of various RNA modifications in the development and progression of cancer. The review particularly focuses on N6-methyladenosine (m⁶A), the most widespread internal modification in RNA, and its regulatory mechanisms.

m⁶Editing is catalyzed by “writers,” including the methyltransferases METTL3, METTL14, and WTAP, and is removed by “erasers” like FTO and ALKBH5. “Readers” such as YTHDF proteins recognize m⁶A sites and mediators of downstream effects, which are crucial for the biological functions of m⁶A. The review highlights that the levels of m⁶A and its regulators are often aberrant in cancer, contributing to disease hallmarks such as proliferation, survival, metastasis, and drug resistance.

Regulatory subunits and post-translational modifications (PTMs) like acetylation, SUMOylation, and phosphorylation can further modulate the activity of m⁶A regulator, influencing its role in cancer. For example, acetylation of ALKBH5 by KAT8 enhances its demethylase activity, promoting tumorigenesis, while METTL3 activity can be regulated by SUMOylation, which impacts cancer cell proliferation and metastasis.

The review also discusses the potential for targeting m⁶A regulator for cancer therapy. Small-molecule inhibitors that target writers, erasers, and m-readers⁶Preclinical models have shown promise. These inhibitors can modulate RNA metabolism, affecting processes such as translation and decay, which in turn can inhibit the malignant phenotypes of cancer cells.

Beyond m⁶A, the review briefly discusses other RNA modifications such as m¹Am⁵C,m⁷G,m⁶Am and that⁴C, which also play an important role in the regulation of gene expression. For example, m1A modification on mRNA is linked to stability and translation, with writers like TRMT6 and erasers like ALKBH3 implicated in cancer progression. Likewise, m5C modification, regulated by authors like NSUN2 and gums like TET1, affects RNA stability and translation, with a potential role in tumor development.

The review highlights the importance of understanding the complex interplay between different RNA modifications and their regulators in the context of cancer. This suggests that a systems biology approach could reveal how these modifications collaborate or compete to influence cancer phenotypes. While research on m⁶A and its regulators are advanced, the study of other RNA modifications and their roles in cancer is still emerging, with much to explore regarding their mechanisms and potential therapeutic implications.

In conclusion, the review provides a detailed overview of the current understanding of RNA modifications in cancer, highlighting the potential to target these modifications for therapeutic intervention. This also highlights the need for continued research to uncover the full range of regulatory mechanisms and their implications in cancer biology.

Provided by Frontiers Journals