Depth Profile Analysis: The Role of RNA Modifications in Cancer Occurrence and Progression

Depth Profile Analysis: The Role of RNA Modifications in Cancer Occurrence and Progression

Recently, in a review article entitled "role of RNA modifications in cancer" published in the international journal Nature Reviews Cancer, scientists from the University of Cambridge in the UK discussed the key role of RNA modifications in cancer.

The specific modification of biological molecules is an effective way to regulate molecular functions. A large number of downstream signaling pathways are affected by DNA and protein modifications. Many enzymes responsible for regulating protein and DNA modification are the key targets of current cancer therapy. The epigenomics of RNA (that is, the study of RNA modification) is a new research field. Although eukaryotic RNA modification has been well known since the 1970s, it was not until the last decade that researchers identified and characterized on mRNA and various non-coding RNAs. The researchers were able to analyze the characteristics of the recognized mRNA and a variety of non-coding RNA. Increasing evidence shows that RNA modification pathways are also misregulated in human cancers and could be ideal targets of cancer therapy.

In this review, the researchers revealed the epitranscriptomic pathway of RNA involved in cancer, and described its biological function and its relationship with disease. Cancer cells have a variety of characteristics, which often give them unlimited growth and avoid the surveillance mechanisms of the host organism. There are eight different key features defined as the hallmarks of cancer. The following figure shows how RNA modification writers, readers and erasers can have either a promoting or an inhibitory effect on these hallmarks. Now researchers are more and more aware that RNA modification and enzymes responsible for deposition, clarification and detection play a key role in different types of cancer.

Figure 1. Eight  different key features were defined as the hallmarks of cancer. Figure 1. Eight different key features were defined as the hallmarks of cancer.

In some cases, a single enzyme often plays the opposite role in different cancer types. Considering the diversity of RNA modification and the types of modified RNA, it may not be surprising. Most of the characteristics of RNA modification players are based on the effect of cell­autonomous hallmarks, such as promoting the proliferation of cancer cells or mediating the invasion and metastasis potential of cancer cells. In particular, N6-­methyladenosine

(m6A) molecules and uridylation enzymes play different roles in cell proliferation, growth and metastasis potential inhibition. These three specific features of cancer cells are easy to investigate but, considering we are only in the earliest stages of this field, researchers are likely to find new non­cell­autonomous RNA modification­dependent functions. For instance, studying the roles of RNA modifications in angiogenesis and the interactions between cancer cells and the host immune system will be particularly interesting. Studying the function of ADAR1 and FTO in regulating cell and systemic immune response may help researchers to use these enzymes as targets to broaden the effect of immunotherapy on cancer.

Recently, elucidating the metabolic processes that cells go through during carcinogenesis may become a central aspect of understanding the mechanism of cancer progression, and great efforts are being made to find ways of targeting cancer metabolism. However, researchers do not know the effect of RNA modification on cancer markers, but the related pathway may be a new way to understand the establishment and regulation mechanism of cancer metabolism. On the contrary, cancer-specific metabolic changes may also directly affect RNA modification and gene expression. It has been shown that RNA modification pathway can regulate cell metabolism by regulating HIF1A mRNA. In particular, m6A modified HIF1A can be stabilized by the combination of m6A modified and YTHDC2, while U34 wobble tRNA modifications can maintain high levels of HIF1 α in melanoma cells. RNA modifying enzymes may be used as sensors of special metabolites, such as METTL16 and FTO. The activity of METTL16 is sensitive to SAM levels and, in turn, it can regulate Sam synthesis by modifying the SAM synthase gene MAT2A. Similarly, FTO is very sensitive to α-ketoglutarate, and it is also inhibited by the oncometabolite 2­hydroxyglutarate.

Figure 2. The  m6A  machinery and its roles in cancer. Figure 2. The m6A machinery and its roles in cancer.

Although RNA epigenetics is still an undeveloped field, many studies have shown that RNA modified pathway can affect the primary and acquired drug tolerance. FTO can protect the function of immunotherapy of melanoma cells, and its down-regulation will increase the sensitivity of cancer cells to anti­PD1 treatment. Similarly, ADAR1 usually needs to inhibit dsRNA derived from endogenous reductive transposons, which can be exploited by cancer cells to escape the immune response. More importantly, the inhibition of ADAR1 will increase the sensitivity of melanoma cells to immunotherapy. Finally, the inactivation of U34 wobble tRNA­modifying enzymes increases sensitivity to BRAF inhibitors in BRAFV600E-driven melanomas and can reverse the acquired resistance of cancer cells to BRAF inhibitors. The results emphasize the potential impact of developing therapeutic agents targeting RNA epigenetics to increase the efficacies of current anticancer therapy.

The many lines of evidence linking dysregulation of RNA epitranscriptomics to cancer strongly suggest that the development of inhibitors targeting RNA pathway may be a fruitful choice and pursuit. The diversity of RNA modification and molecular pathways involved in RNA modification gives researchers hope that this is only the beginning of the era of RNA epigenetics in cancer therapy.

Reference

  1. Barbieri, I., Kouzarides, T. Role of RNA modifications in cancer. Nat Rev Cancer 20, 303-322 (2020).

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