Cancer, a disease with global impact, is intricately linked to dysregulated gene expression, which is affected by both genetic mutations and epigenetic changes, including RNA modifications. A comprehensive review published in The limits of medicine reveals the importance of different RNA modifications in cancer development and progression. The review focuses particularly on N6-methyladenosine (m⁶A), the most common internal modification in RNA and its regulatory mechanisms.

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

Regulatory subunits and post-translational modifications (PTMs) such as acetylation, SUMOylation and phosphorylation can further modulate the activity of m⁶A regulator, which affects their roles in cancer. For example, acetylation of ALKBH5 by KAT8 increases its demethylase activity, which promotes tumorigenesis, while METTL3 activity can be regulated by SUMOylation, which affects cancer cell proliferation and metastasis.

The review also discusses the potential of targeting m⁶A regulator for cancer therapy. Small molecule inhibitors aimed at writers, erasers and readers of m⁶A has shown promise in preclinical models. 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 touches on other RNA modifications such as m¹A, m⁵C, m⁷G, m⁶Am and ac⁴C, which also play significant roles in regulating gene expression. For example, m1A modification on mRNA is linked to stability and translation, with writers such as TRMT6 and erasers such as ALKBH3 implicated in cancer progression. Similarly, the m5C modification, regulated by writers like NSUN2 and eraser like TET1, affects RNA stability and translation, with potential roles 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. It suggests that a systems biology approach can reveal how these modifications cooperate or compete with each other 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, and emphasizes the potential of targeting these modifications for therapeutic intervention. It also points to the need for further research to uncover the full spectrum of regulatory mechanisms and their implications in cancer biology.

Provided by Frontiers Journals