RNA Epigenetics in Cancer: Current Knowledge and Therapeutic Implications

Abstract

RNA epigenetics, also referred to as epitranscriptomics, has emerged as a critical regulatory layer in cancer biology, extending beyond the scope of traditional DNA and histone modifications. It encompasses a series of dynamic posttranscriptional processes-including RNA biosynthesis, splicing, transport, stability, degradation, translation, and chemical modifications-orchestrated by RNA-binding proteins (RBPs) and noncoding RNAs (ncRNAs). Collectively, these mechanisms influence mRNA fate, shape transcriptional output, and reprogram the tumor microenvironment. Importantly, both coding RNA and ncRNA are themselves subjected to epigenetic regulation, forming intricate feedback loops that contribute to oncogenesis, immune evasion, metastasis, and therapeutic resistance. In this review, we systematically synthesize the current understanding of RNA metabolism and RNA epigenetic modifications during tumor progression, with a particular focus on the roles of RBPs and RNA modifications. Furthermore, we highlight recent advances in RNA-based therapeutic strategies, including mRNA vaccines, antisense oligonucleotides, siRNAs, and circRNA scaffolds. These innovative approaches offer promising avenues for targeting transcriptionally active yet genomically "undruggable" cancer drivers. Together, our synthesis provides a comprehensive framework for understanding RNA epigenetics in tumor biology and lays the groundwork for precision oncology guided by transcriptome plasticity.

Keywords: RNA epigenetics; RNA metabolism; pan‐cancer; targeted therapy.

FIGURE 1

RNA biogenesis during the cancer progression. The figure illustrates histone modifications and DNA methylation involved in cancer progression. The upper part depicts histone modifications, where histones exist as octamers composed of core histone proteins (H2A, H2B, H3, and H4). The N‐terminal tails of these histones can be chemically modified. This section highlights histone methylation and acetylation‐related enzymes implicated in tumor development, along with representative therapeutic agents targeting these modifications. The lower part of the figure focuses on DNA methylation in cancer. DNA methylation typically represses gene expression at methylated loci. DNA methyltransferases (DNMTs) function as “writers” that catalyze the addition of methyl groups, while the ten‐eleven translocation (TET) family of enzymes act as “erasers” that remove DNA methylation marks. Together, histone modifications and DNA methylation cooperatively regulate the expression of target genes, thereby contributing to tumor progression. The figure also lists cancer‐related genes that are known to be regulated by these epigenetic mechanisms.

FIGURE 2

Epitranscriptomic regulation of mRNA stability and degradation in cancer. This schematic depicts the epitranscriptomic modifications that regulate mRNA fate, particularly in the context of cancer biology. Multiple RNA modifications—5‐methylcytosine (m⁵C), N⁶‐methyladenosine (m⁶A), 7‐methylguanosine (m⁷G), and N¹‐methyladenosine (m¹A)—are installed by specific writer enzymes such as NSUNs (for m⁵C), METTL3/METTL14 (for m⁶A), and METTL1 (for m⁷G), and are recognized by reader proteins like YTHDF2. These modifications influence mRNA stability and decay through the recruitment of RBPs and interaction with ARE‐binding proteins (AREBPs), including HuR, YBX1, FXR1, and ELAVL3, which bind AU‐rich elements (AREs) in the 3′ untranslated region (3′‐UTR). Stabilized transcripts are processed into peptides via ribosomal translation, whereas mRNAs marked for degradation are directed to exo‐ and endonucleases. Targeting RNA stability using agents such as MS‐444, DHTS, and Okicenone, or siRNA/sgRNA‐based approaches, represents a promising avenue for RNA‐targeted cancer therapies.

FIGURE 3

Schematic overview of RNA splicing regulation and its therapeutic targets in cancer. This diagram illustrates the dynamic assembly of the spliceosome on pre‐mRNA, involving key small nuclear ribonucleoproteins (snRNPs: U1, U2, U4, U5, and U6) and splicing factors (SFs), including serine/arginine‐rich (SR) proteins and heterogeneous nuclear ribonucleoproteins (hnRNPs). Regulatory elements such as exonic/intronic splicing enhancers (ESE, ISE) and silencers (ESS, ISS) modulate splice site recognition. Core splicing factor SF3B1, a frequent mutational hotspot in cancer, is highlighted. Cancer‐associated RBPs and splicing factors (SFs) such as ZRSR2, PRPF8, and HNRNPCL1 contribute to oncogenic alternative splicing. Small‐molecule inhibitors targeting splicing machinery (e.g., H3B‐8800, Meayamycin D, E7107) and PRMT inhibitors (e.g., OTS964, (R)‐SKBG‐1) are shown as emerging therapeutic strategies. Aberrant splicing events impact key cancer‐related genes including ASXL1, CD44 variants, FGFR2 isoforms, and CEACAM1‐L, underscoring the pathological relevance of splicing dysregulation in tumorigenesis.

FIGURE 4

Mechanisms of RNA nuclear export and extracellular RNA‐mediated intercellular communication in cancer. This illustration outlines the two interconnected processes of RNA nuclear export and extracellular RNA (exRNA) trafficking in the tumor microenvironment. (Left) In the nucleus, messenger RNA (mRNA) transcripts are exported to the cytoplasm through the nuclear pore complex (NPC), where nucleoporins such as Nup88 coordinate with RNA‐binding proteins (RNPs) and export factors including THOC1/TREX, ALY, CRM1, and eIF4E. The export process can be selectively inhibited by agents such as selective inhibitors of nuclear export (SINEs). (Right) In the extracellular compartment, cancer cells release exRNAs (e.g., miR‐21, miR‐100, miR‐125b) via extracellular vesicles (EVs), which mediate cell‐to‐cell communication. These vesicles are taken up by stromal components like cancer‐associated fibroblasts (CAFs) and immune cells, influencing tumor progression, immune modulation, and microenvironmental remodeling. Specific exRNAs, such as miR‐145 and PIAT from CAFs or Y RNA and miR‐24 from tumor cells, contribute to the dynamic signaling network that sustains malignancy.

FIGURE 5

The roles of noncoding RNAs in cancer progression across tumor types. miRNAs regulate mRNA stability and translation through direct base pairing. Both circRNAs and lncRNAs can function as miRNA sponges to inhibit miRNA activity, while also participating in RNA metabolism via interactions with RNA‐binding proteins. piRNAs form complexes with PIWI proteins to regulate mRNA stability, splicing, and translation. Double‐stranded eRNAs are classified as sense or antisense; antisense eRNAs recruit DNMT1 to promote DNA methylation and gene transcription, while sense eRNAs enhance transcription via promoter binding. tRFs have been associated with poor prognosis in multiple cancers, although their molecular mechanisms require further investigation. This figure summarizes representative noncoding RNAs implicated in tumorigenesis across diverse cancer types.