RNA modifications and their role in cancer development

Frontiers JournalsOct 25 2024

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

m⁶A modification is catalyzed by "writers," including methyltransferases METTL3, METTL14, and WTAP, and is removed by "erasers" like FTO and ALKBH5. "Readers" such as YTHDF proteins recognize m⁶A sites and mediate downstream effects, which are crucial for the biological functions of m⁶A. The review underscores that the levels of m⁶A and its regulators are often aberrant in cancer, contributing to hallmarks of the disease 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 regulators, influencing their roles in cancer. For instance, acetylation of ALKBH5 by KAT8 enhances its demethylase activity, promoting tumorigenesis, while METTL3 activity can be regulated by SUMOylation, impacting cancer cell proliferation and metastasis.

The review also discusses the potential of targeting m⁶A regulators for cancer therapy. Small molecule inhibitors that target writers, erasers, and readers of m⁶A have shown promise in preclinical models. These inhibitors can modulate RNA metabolism, affecting processes like translation and decay, which in turn can inhibit cancer cell malignant phenotypes.

Beyond m⁶A, the review briefly touches on other RNA modifications such as m¹A, m⁵C, m⁷G, m⁶Am, and ac⁴C, which also play significant roles in gene expression regulation. For example, m¹A modification on mRNA is linked to stability and translation, with writers like TRMT6 and erasers like ALKBH3 implicated in cancer progression. Similarly, the m5C modification, regulated by writers like NSUN2 and erasers 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 could reveal how these modifications collaborate or compete with each other to influence cancer phenotypes. While research on m⁶A and its regulators is advanced, the study of other RNA modifications and their roles in cancer is still emerging, with much to be explored regarding their mechanisms and potential therapeutic implications.

In conclusion, the review provides a detailed overview of the current understanding of RNA modifications in cancer, emphasizing 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.