Epitranscriptomics and cervical cancer: the emerging role of m6A, m5C and m1A RNA modifications

Abstract

Cervical cancer (CC), one of the most prevalent and detrimental gynaecologic cancers, evolves through genetic and epigenetic alterations resulting in the promotion of oncogenic activity and dysfunction of tumour-suppressing mechanisms. Despite medical advancement, the prognosis for advanced-stage patients remains extremely low due to high recurrence rates and resistance to existing treatments. Thereby, the search for potential prognostic biomarkers is heightened to unravel new modalities of CC pathogenesis and to develop novel anti-cancer therapies. Epitranscriptomic modifications, reversible epigenetic RNA modifications, regulate various biological processes by deciding RNA fate to mediating RNA interactions. This narrative review provides insight into the cellular and molecular roles of endogenous RNA-editing proteins and their associated epitranscriptomic modifications, especially N⁶-methyladenosine (m⁶A), 5-methylcytosine (m⁵C) and N¹-methyladenosine (m¹A), in governing the development, progression and metastasis of CC. We discussed the in-depth epitranscriptomic mechanisms underlying the regulation of over 50 RNAs responsible for tumorigenesis, proliferation, migration, invasion, survival, autophagy, stemness, epithelial-mesenchymal transition, metabolism (glucose, lipid, glutamate and glutamine), resistance (drug and radiation), angiogenesis and recurrence of CC. Additionally, we provided a concise overview of the therapeutic potential of targeting the altered expression of endogenous RNA-editing proteins and aberrant deposition of RNA modifications on both coding and non-coding RNAs in CC.

Keywords: RNA modifications; RNA-editing proteins; anti-cancer therapies; cervical cancer; diagnostic biomarkers; epitranscriptomics; gene expression; m1A; m5C; m6A.

Figure 1.

Epitranscriptomic mechanism in cervical cancer cells. DNA is transcribed into RNA, which undergoes various modifications including N⁶-methyladenosine (m⁶A), 5-methylcytosine (m⁵C) and N¹-methyladenosine (m¹A). These RNA modifications are regulated by specific endogenous RNA-editing proteins, categorized as: (1) ʻwriters', facilitating modification deposition; (2) ʻerasers', removing modifications; and (3) ʻreaders', interacting with modified RNA. This epitranscriptomic mechanism intricately governs RNA fate, influencing processes such as export, localization, stabilization, translation and degradation. Consequently, this modulation of genetic expression profoundly impacts cellular functions in cervical cancer. Created with BioRender.com.

Figure 2.

OncoPrint depicting the landscape of endogenous RNA-editing proteins responsible for N⁶-methyladenosine (m⁶A) modification in cervical cancer patients. Writers including CBLL1, METTL3/4/14/16, RBM15, VIRMA, WTAP and ZC3H13, as well as erasers ALKBH3/5 and FTO, are shown alongside readers such as ABCF1, ELAVL1, FMR1, FXR1, HNRNPA2B1, HNRNPC, IGF2BP1/2/3, LRPPRC, YTHDC1/2 and YTHDF1/2/3. Each column represents an individual patient sample and displays a comprehensive overview of the mutation spectrum, diagnosis age (years), overall survival (months), radiation therapy and genetic alterations, along with mRNA expression levels of m⁶A-associated endogenous RNA-editing proteins. mRNA expression is represented by z-scores relative to diploid samples (RNA Seq V2 RSEM). The Cancer Genome Atlas Program (TCGA) data of 297 cervical cancer patients were analysed and visualized using cBioPortal for Cancer Genomics (Refs 115, 116, 117).

Figure 3.

OncoPrint depicting the landscape of endogenous RNA-editing proteins responsible for 5-methylcytosine (m⁵C) modification in cervical cancer patients. Writers including DNMT1, DNMT3A/B, NOP2, NSUN2/3/4/5/6/7 and TRDMT1, as well as eraser TET2, are shown alongside readers such as ALYREF and YBX1. Each column represents an individual patient sample and displays a comprehensive overview of the mutation spectrum, diagnosis age (years), overall survival (months), radiation therapy and genetic alterations, along with mRNA expression levels of m⁶A-associated endogenous RNA-editing proteins. mRNA expression is represented by z-scores relative to diploid samples (RNA Seq V2 RSEM). The Cancer Genome Atlas Program (TCGA) data of 297 cervical cancer patients was analysed and visualized using cBioPortal for Cancer Genomics (Refs 115, 116, 117).

Figure 4.

OncoPrint depicting the landscape of endogenous RNA-editing proteins responsible for N¹-methyladenosine (m¹A) modification in cervical cancer patients. Writers including TRMT10C, TRMT6 and TRMT61A, as well as eraser ALKBH3, are shown alongside readers such as YTHDC1 and YTHDF2. Each column represents an individual patient sample and displays a comprehensive overview of the mutation spectrum, diagnosis age (years), overall survival (months), radiation therapy and genetic alterations, along with mRNA expression levels of m⁶A-associated endogenous RNA-editing proteins. mRNA expression is represented by z-scores relative to diploid samples (RNA Seq V2 RSEM). The Cancer Genome Atlas Program (TCGA) data of 297 cervical cancer patients was analysed and visualized using cBioPortal for Cancer Genomics (Refs 115, 116, 117).