Epigenetics Research: Open Access
Open Access

Non-Coding RNA Regulation in Colorectal Cancer: Epigenetic Mechanisms and Clinical Applications

Frances Saltzman^{* *}Correspondence: Frances Saltzman, Department of Biomedical Sciences, University of Cartagena, Cartagena, Colombia, Email:

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Description

Non-coding RNAs, including microRNAs and long non-coding RNAs, play pivotal roles in colorectal cancer through complex epigenetic regulatory networks that influence tumor initiation, progression, and treatment response. Colorectal Cancer (CRC) represents the third most common cancer worldwide, with its development involving a complex interplay between genetic and epigenetic alterations. Among these, non-coding RNAs (ncRNAs) have emerged as key regulatory molecules that control gene expression through various epigenetic mechanisms.

MicroRNAs (miRNAs) are perhaps the most well-characterized ncRNAs in CRC. Several miRNAs function as tumor suppressors, including miR-34a, miR-143, and miR-145, which are frequently silenced through promoter hypermethylation in CRC. The restoration of these miRNAs through demethylating agents has shown therapeutic potential in preclinical models. Conversely, oncogenic miRNAs such as miR-17-92 cluster members are overexpressed in CRC and contribute to tumor progression by targeting cell cycle checkpoints and apoptosis pathways.

Long non-coding RNAs (lncRNAs) represent another important class of epigenetic regulators in CRC. The lncRNA hotair is significantly upregulated in CRC and promotes metastasis by recruiting chromatin-modifying complexes to target gene promoters. Hotair interacts with both PRC2 and LSD1 complexes, leading to H3K27me3 deposition and H3K4me2 removal at tumor suppressor gene loci. This dual mechanism of gene silencing makes hotair an attractive therapeutic target.

The lncRNA MALAT1 is another key player in CRC progression. MALAT1 regulates alternative splicing and nuclear organization, influencing the expression of genes involved in cell proliferation and invasion. Recent studies have shown that MALAT1 can be targeted using antisense oligonucleotides, leading to reduced tumor growth and metastasis in mouse models.

Circular RNAs (circRNAs) have recently emerged as important regulators of CRC biology. These stable, non-coding transcripts function as miRNA sponges, sequestering miRNAs away from their target mRNAs. CircRNA as, for example, contains multiple binding sites for miR-7 and prevents miR-7-mediated suppression of oncogenes. The dysregulation of circRNA networks in CRC creates new opportunities for therapeutic intervention. The epigenetic regulation of ncRNAs themselves adds another layer of complexity to CRC biology. DNA methylation of miRNA promoters is a common mechanism of tumor suppressor miRNA silencing. The miR-34a promoter is hypermethylated in approximately 70% of CRC cases, leading to loss of p53-mediated tumor suppression. Similarly, the promoters of miR-143 and miR-145 are subject to methylationmediated silencing.

Histone modifications also play crucial roles in ncRNA regulation. The H3K27me3 mark, deposited by PRC2, silences multiple tumor suppressor miRNAs in CRC. EZH2 gene inhibition can restore the expression of these miRNAs, leading to tumor growth suppression. This finding has led to clinical trials evaluating EZH2 inhibitors in CRC patients. The clinical applications of ncRNA research in CRC are expanding rapidly. Circulating miRNAs in plasma and serum have shown promise as biomarkers for CRC diagnosis, prognosis, and treatment monitoring. A panel of miRNAs including miR-21, miR-92a, and miR-29a can distinguish CRC patients from healthy controls with high accuracy.

Conclusion

Therapeutic targeting of ncRNAs is becoming increasingly feasible. Antisense oligonucleotides, miRNA mimics, and miRNA inhibitors are being developed for CRC treatment. The delivery of these agents remains challenging, but advances in nanoparticle technology and conjugation strategies are improving their therapeutic potential. Future research should focus on understanding the complex regulatory networks involving ncRNAs and developing combination therapies that target multiple epigenetic pathways simultaneously. The integration of ncRNA profiling into clinical practice will be essential for personalized CRC treatment approaches.