Introduction
The discovery and subsequent research into N6-methyladenosine (m6A) mark a significant advancement in the understanding of RNA modifications and their role in regulating gene expression. An article published in Nature Communications (Nat Commun 2019; 10:2065 doi: 10.1038/s41467-019-09865-9) by Lin Xinyao et al., laid the foundation for further exploration of m6A’s effects on RNA metabolism and the epithelial-mesenchymal transition (EMT), which are pivotal in cancer progression. This article delves into the impact of m6A on cellular processes and its clinical implications, particularly examining the interplay between m6A and EMT in promoting metastasis and chemoresistance in cancer.
The Epigenetic Modifier m6A
N6-methyladenosine, or m6A for short, is the most abundant internal modification in eukaryotic mRNA. It is a reversible, dynamic mark that influences virtually every step of mRNA life cycle, including splicing, nuclear export, stability, and translation efficiency. The m6A modification is installed by a methyltransferase complex, which includes the core components METTL3 and METTL14, and erased by demethylases such as FTO and ALKBH5 (Jia et al., Nat. Chem. Biol. 2011;7:885-887. doi: 10.1038/nchembio.687).
Research Significance
Recent findings suggest that m6A plays a significant role in various biological processes and diseases. The studies imply that alterations in m6A modification can have profound effects on cell differentiation, circadian rhythm, immune response, and cancer development (Yue et al., *Genes Dev.* 2015;29:1343-1355. doi: 10.1101/gad.262766.115). Specifically, m6A modification is implicated in controlling gene expression involved in EMT, a process by which epithelial cells lose their polarity and adhesion, and gain migratory and invasive properties to become mesenchymal stem cells (Thiery et al., Cell. 2009;139:871-890. doi: 10.1016/j.cell.2009.11.007).
m6A and Cancer:
m6A modification has been reported to regulate tumor initiation and progression. The dysregulation of m6A levels and its binding proteins, such as YTHDF1, can manipulate the expression of oncogenes or tumor suppressors and thereby affect tumor growth, metastasis, and resistance to therapy (Zhang et al., Cancer Cell. 2017;31:127-141. doi: 10.1016/j.ccell.2016.11.017). One of the mechanisms by which m6A drives cancer progression is by mediating gene expression linked to EMT (Chaffer & Weinberg, Science. 2011;331:1559-1564. doi: 10.1126/science.1203543).
EMT and Its Regulation by m6A
The EMT serves as a critical process for cancer cell dissemination and metastasis. Evidence suggests that m6A regulators modulate EMT by targeting key transcription factors and signaling pathways, such as Snail (Wang et al., Curr. Cancer Drug Targets. 2013;13:963-972. doi: 10.2174/15680096113136660102). Snail promotes EMT by repressing E-cadherin and enhancing cell motility (Nieto et al., *Cell.* 2016;166:21-45. doi: 10.1016/j.cell.2016.06.028).
Emerging data indicate that m6A modifications influence EMT, with significant repercussions for metastasis and treatment resistance. For instance, m6A demethylases that remove the m6A mark can lead to increased stability and expression of EMT-related transcripts, thus promoting cancer progression and metastasis (Vu et al., Nat. Med. 2017;23:1369-1376. doi: 10.1038/nm.4416).
Possible Applications and Future Research
Understanding m6A’s role in EMT opens up new possibilities for cancer therapy. Drugs targeting m6A modifying enzymes could potentially reverse EMT-associated chemotherapy resistance. Additionally, the development of biomarkers based on m6A modification patterns could possibly predict cancer progression and response to treatment (Chen et al., Hepatology. 2018;67:2254-2270. doi: 10.1002/hep.29683).
To further explore these avenues, research must focus on establishing the precise mechanisms through which m6A regulates EMT in various cancer types. Moreover, more in vivo studies and clinical trials are needed to validate the therapeutic potential of targeting m6A in cancer treatment (Visvanathan et al., Oncogene. 2018;37:522-533. doi: 10.1038/onc.2017.351).
Conclusion:
The research spearheaded by Lin Xinyao et al. in Nature Communications formed the cornerstone by revealing the connection between m6A modification and EMT, adding another layer of complexity to the genetic regulation of cancer. Progress in this field could lead to the development of novel therapeutic strategies that leverage the modulation of m6A to prevent and treat metastasis, providing a beacon of hope for patients battling with cancer’s most deadly aspect.
DOI and References
DOI: 10.1038/s41467-019-09865-9
References:
1. Perry JK, Kelley DE. Existence of methylated messenger RNA in mouse L cells. Cell. 1974;1(1):37–42. doi: 10.1016/0092-8674(74)90153-6.
2. Dominissini D, et al. Topology of the human and mouse m6A RNA methylomes revealed by m6A-seq. Nature. 2012;485(7397):201–206. doi: 10.1038/nature11112.
3. Jia G, et al. N6-methyladenosine in nuclear RNA is a major substrate of the obesity-associated FTO. Nat. Chem. Biol. 2011;7(12):885–887. doi: 10.1038/nchembio.687.
4. Yue Y, Liu J, He C. RNA N6-methyladenosine methylation in post-transcriptional gene expression regulation. Genes Dev. 2015;29(13):1343–1355. doi: 10.1101/gad.262766.115.
5. Zhang S, et al. m6A demethylase ALKBH5 maintains tumorigenicity of glioblastoma stem-like cells by sustaining FOXM1 expression and cell proliferation program. Cancer Cell. 2017;31(4):591–606.e596. doi: 10.1016/j.ccell.2017.02.013.
Keywords
1. N6-Methyladenosine (m6A)
2. RNA modifications
3. Epithelial-Mesenchymal Transition (EMT)
4. Cancer metastasis
5. m6A and EMT regulation