Microbiology, Virology, Immunology, Fergana Medical Institute of Public Health, Uzbekistan.
This review article examines the fundamental role of non-coding RNAs (ncRNAs), particularly microRNAs (miRNAs), as major mediators of epigenomic alteration and their causal relationship with oncogenesis. Epigenetics — encompassing DNA methylation, histone modifications, nucleosome remodeling, and ncRNA-mediated regulation — governs heritable changes in gene expression without altering the underlying DNA sequence. When these regulatory mechanisms are disrupted, they contribute to the initiation, progression, and metastasis of various human malignancies. This article reviews the mechanistic interplay between epigenetic dysregulation and tumorigenesis across seven major cancer types: breast, cervical, prostate, lung, liver, colon, and pancreatic cancers. Furthermore, it highlights emerging therapeutic strategies, including epidrugs and plant-derived miRNA-based interventions, as promising avenues for precision oncology.
The term "epigenetics" was coined by Conrad Waddington in 1942 to describe heritable phenotypic changes that do not correspond to alterations in the genetic code. The revised definition describes epigenetics as "the study of changes in gene function that are mitotically and/or meiotically heritable but do not involve a change in DNA sequence." Disruptions in epigenetic processes can result in altered gene function and malignant cellular transformation.[3]
Epigenetic abnormalities — in addition to genetic alterations — are now recognized as key drivers in the initiation and progression of cancer. The epigenome, which encompasses DNA methylation, histone modifications, nucleosome positioning, and non-coding RNA expression (particularly microRNAs), has been extensively reprogrammed due to recent advances in genomic profiling technologies.[1,4]
Cancer is a heterogeneous group of diseases characterized by dysregulation of key cellular pathways involved in cell cycle regulation, proliferation, differentiation, DNA repair, and programmed cell death. Malignant transformation, tumor initiation, progression, and metastasis are coordinated through complex networks of genetic and epigenetic interactions.[2,5]
Aberrant epigenetic reprogramming has been linked to developmental disorders such as Beckwith-Wiedemann and Silver-Russell syndromes, as well as complex multifactorial diseases including metabolic syndrome, cardiovascular disease, and neurological disorders. Non-mutational epigenetic reprogramming has been identified as a hallmark of cancer and a potential driver of mutational events that promote genomic instability and malignant transformation.[1,2]
Figure 1. Core epigenetic mechanisms — DNA methylation, histone modifications, chromatin remodeling, and non-coding RNA regulation — that govern heritable changes in gene expression.
2. Non-Coding RNAs and MicroRNAs
MicroRNAs (miRNAs) are small, non-coding RNA molecules averaging 20 nucleotides in length that suppress translation or affect mRNA stability. They have been identified as "master" regulators of a wide range of cellular functions. MiRBase version 19 contains 21,264 entries spanning 193 species, including approximately 2,000 human miRNA sequences. miRNA biogenesis plays a central role in regulating gene expression.[21,22]
Figure 2. The microRNA biogenesis pathway, from nuclear transcription of pri-miRNA to RISC-mediated mRNA repression in the cytoplasm.
2.1 Dietary and Nutritional Influence on miRNAs
All-trans-retinoic acid (ATRA), a vitamin A metabolite, mediates effects on cell proliferation and differentiation through miRNA pathways; similar expression patterns have been observed in patients treated with ATRA and chemotherapy. Folate (vitamin B9) is thought to have cancer-preventive properties — high dietary folate levels have been linked to a lower risk of gastrointestinal tumors — and emerging data suggest miRNA expression levels correlate with adequate intake of specific nutritional agents.[24][24]
Vitamin D may exert protective effects by influencing miRNA expression. Vitamin D3 specifically downregulates miR-181a and miR-181b in human myeloid leukemia cells, increasing p27KIP1 and p21CIP1 and inducing cell cycle arrest. Dietary agents such as butyrate, flavonoids, and curcumin can also alter the epigenetic landscape by modulating gene/miRNA transcription, resulting in changes to cell proliferation, differentiation, and survival.[23]
2.2 miRNAs in Oncogenesis
Abnormal miRNA expression has been linked to colon, liver, lung, breast, prostate, and pancreatic cancers. miRNAs have also been associated with tumor location, mutation status of tumor suppressor genes/oncogenes, and cancer stage. Nuclear-activated miRNAs (NamiRNAs) bind to promoter and enhancer regions to promote gene expression, and some miRNAs target DNA methyltransferases (DNMTs), affecting gene expression at both the transcriptional and post-transcriptional levels.[26][25]
Plant bioengineering to produce miRNAs with desired sequences is a well-established technology currently applied in food crop research. Edible plants as therapeutic miRNA delivery vehicles are feasible and represent a low-cost alternative to current synthetic RNA production methods, with significant potential in basic, translational, and clinical applications. Deregulation of miRNAs, common in human cancer, significantly disrupts gene-regulatory balance, contributing to oncogenesis and cancer progression.[25][27,28]
3. Epigenetic Alterations in Breast Cancer
Epigenetic changes are a leading cause of breast cancer. Non-coding RNAs, particularly miRNAs, play a critical role in post-transcriptional regulation of breast cancer tumorigenesis, progression, and metastasis. miRNAs (17–25 nucleotides in length) regulate gene expression in both normal and malignant cells. RNA Polymerase II promotes the transcription of primary miRNAs. Tumor suppressor miRNAs, such as miR-4458 (linked to the SOCS1 signaling pathway), are downregulated in breast cancer, whereas oncogenic miRNAs such as miR-214 (linked to the PI3K/Akt/mTOR pathway) are upregulated.[6][6]
Figure 3. miRNA dysregulation in breast cancer: tumor-suppressor miR-4458 is downregulated while oncogenic miR-214 activates the PI3K/AKT/mTOR axis, driving tumor progression and metastasis.
Elevated levels of circulating nucleosomes are associated with tumor recurrence and metastasis in breast cancer. In breast cancer cell lines, 2′-O methylation in ribosomal RNA (rRNA) is hypermodified and associated with altered protein translation. tRNA modifications, such as m5C and 5-methoxycarbonylmethyluridine (mcm5U), have also been reported and are associated with translational dysregulation.[6]
Mutations in histone methyltransferases have stimulated the development of epidrugs targeting a broad range of chromatin regulators. Epigenetic agents can induce cell death in response to endocrine therapy. Tamoxifen-induced autophagy increases cancer cell death, though it may also drive tamoxifen-resistant breast cancer phenotypes.[6][7]
4. Epigenetic Alterations in Cervical Cancer
Throughout cervical carcinogenesis, both the Human Papillomavirus (HPV) and host genomes undergo epigenetic changes including global DNA hypomethylation, tumor suppressor gene hypermethylation, and histone modifications. HPV exploits the host’s epigenetic machinery to promote viral persistence, evade immune surveillance, and drive oncogenic transformation.[8]
The viral oncoproteins E6 and E7 play critical roles: they not only disrupt tumor suppressor pathways (particularly p53 and Rb), but also alter the host epigenetic landscape to promote malignancy. Non-coding RNAs, particularly miRNAs and lncRNAs, are increasingly recognized as important epigenetic regulators in cervical cancer development.
MiRNAs such as miR-34a, miR-203, and miR-375 are frequently downregulated in HPV-positive cervical cancers through direct targeting by HPV oncoproteins or promoter hypermethylation. Conversely, oncogenic miRNAs such as miR-21 are upregulated and contribute to tumor progression. LncRNAs such as HOTAIR, MALAT1, and PVT1 are also dysregulated in HPV-associated cervical cancer and function by recruiting epigenetic modifiers to specific genomic loci, altering chromatin states and gene expression.[9,10,11]
Figure 4. HPV-driven epigenetic reprogramming in cervical cancer. E6 and E7 oncoproteins inactivate p53 and Rb, while ncRNA dysregulation (downregulation of miR-34a/203/375 and upregulation of miR-21, HOTAIR, MALAT1, PVT1) promotes carcinogenesis.
5. Epigenetic Alterations in Prostate Cancer
Castration-resistant prostate cancer (CRPC) represents a disease state that develops after tumor progression on androgen deprivation therapy. Despite significant therapeutic advances, the median survival of metastatic CRPC (mCRPC) is approximately three years. Up to 15–20% of mCRPC patients develop non-androgen receptor (AR)-driven disease as a mechanism of treatment resistance, sometimes with pathologic features of small cell neuroendocrine prostate cancer (NEPC).[12]
Single nucleotide polymorphisms (SNPs) identified within lncRNA genes are associated with prostate cancer, suggesting a role in tumor evolution. A meta-analysis of data from 474 patients revealed that lncRNAs SNHG3, SNHG7, NEAT1, PCAT6, and NORAD were overexpressed in prostate cancer and associated with lower overall survival and adverse prognostic value.[12]
DNA hypermethylation of cytosine-guanine (CpG)-rich islands within gene promoter regions is widespread during neoplastic transformation of prostate cells, suggesting that treatment-induced restoration of a normal epigenome may be clinically beneficial.[12]
6. Epigenetic Alterations in Lung Cancer
Lung cancer results from the accumulation of genetic and epigenetic events in respiratory epithelium. Tumor suppressor gene inactivation via promoter hypermethylation is a hallmark of lung cancer and an early step in the carcinogenic process.[13]
Frequently studied genes in the context of promoter methylation in lung cancer include p16INK4a, RASSF1A, APC, RARβ, CDH1, CDH13, DAPK, FHIT, and MGMT. While p16INK4a is frequently methylated, mutated, or deleted in non-small cell lung cancer (NSCLC) — with an estimated prevalence of alteration around 60% — p14arf (also encoded on the CDKN2A gene) is less frequently inactivated (8–30% of NSCLC).[14,15]
The three main epigenetic targets associated with lung cancer treatment are DNA methyltransferase (DNMT), histone lysine methyltransferase (KMT), and histone lysine acetyltransferase. Epigenetic-based drugs are frequently employed in combination with targeted therapies and chemotherapy to improve efficacy and reduce resistance.[14]
Figure 5. Promoter hypermethylation silences tumor-suppressor genes (p16INK4a, RASSF1A, APC, MGMT, CDH13) in lung cancer. DNMT and HDAC inhibitor epidrugs reactivate these tumor suppressors.
7. Epigenetic Alterations in Liver Cancer
The liver continuously adapts to circadian cues, metabolic processes, microbiota changes, and external factors such as viral infections and xenobiotics, necessitating ongoing repair and regeneration. As a result, the hepatic epigenome is highly sensitive to its dynamic environment. Metabolic risk factors including obesity, excessive alcohol consumption, and viral hepatitis alter the hepatic epigenome.
Epigenomic changes — including DNA methylation, chromatin modification, miRNA dysregulation, and lncRNA alterations — promote uncontrolled cell growth, invasion, and metastasis, and drive the progression from chronic liver inflammation and fibrosis to hepatocellular carcinoma (HCC). In HCC, genes such as CDKN2A, RASSF1A, and SOCS1 are frequently hypermethylated, resulting in loss of function in cell cycle and apoptosis pathways. LncRNAs such as HULC, MALAT1, and HOTAIR are overexpressed and function as oncogenic drivers by sponging tumor-suppressive miRNAs or interacting with chromatin modifiers.[16][16]
Precision cancer management strategies for HCC have advanced to include precision surgical resection, subtype-based targeted molecular therapy, and immunotherapy. Sorafenib, a multi-tyrosine kinase inhibitor (TKI), marked a milestone in systemic therapy as a first-line treatment.[17]
8. Epigenetic Alterations in Colon Cancer
Colorectal cancer (CRC) arises from the accumulation of genetic and epigenetic changes in colon epithelial cells, which progressively transform into adenocarcinomas. Other types of premalignant lesions, such as serrated polyps, also carry a high potential for malignant transformation.[18]
Efforts to characterize the molecular features of colorectal cancers have yielded clinical assays that detect KRAS mutations, used to guide therapy with anti-EGFR monoclonal antibodies in patients with metastatic CRC. Certain medications, including hormone therapies and specific chemotherapy agents, can increase the long-term risk of developing secondary CRC, particularly when combined with radiotherapy.[19]
9. Epigenetic Alterations in Pancreatic Cancer
Pancreatic ductal adenocarcinoma (PDAC) represents one of the most challenging malignancies in modern oncology. In pancreatic cancer, tumor suppressor gene (TSG) promoter hypermethylation silences critical regulatory genes, whereas global hypomethylation can inappropriately activate oncogenes. Abnormal histone methylation and acetylation patterns disrupt chromatin structure and drive tumorigenesis.[20]
TSG silencing by promoter hypermethylation is a common and critical event in pancreatic cancer. A classic example is the CDKN2A gene (encoding p16INK4a), a key cell cycle regulator. Hypermethylation of the CDKN2A promoter leads to its silencing, contributing to uncontrolled cell division, and is commonly observed in PDAC.[20]
Global hypomethylation in pancreatic cancer leads to chromosomal instability, activation of transposable elements, and inappropriate expression of normally silenced oncogenes. Initial clinical trials at stages I–III with DNMT, HDAC, and HAT inhibitors are currently underway, paving the way for the development of novel ‘epidrugs’ for pancreatic cancer patients.[20]
CONCLUSION
Epigenetics plays an indispensable role in the initiation, progression, and metastasis of cancer by altering gene expression without modifying the DNA sequence. DNA methylation, histone modification, chromatin remodeling, and non-coding RNA regulation — particularly microRNAs — have been identified as major contributors to tumor development. Abnormal epigenetic reprogramming disrupts core cellular processes, including cell cycle regulation, apoptosis, DNA repair, and differentiation, ultimately driving malignant transformation.
Across breast, cervical, prostate, lung, liver, colon, and pancreatic cancers, distinct epigenetic signatures have been characterized. Promoter hypermethylation commonly silences tumor suppressor genes, while hypomethylation or dysregulated miRNA expression activates oncogenes. Viral infections (e.g., HPV), environmental exposures, dietary components, and metabolic disorders all converge to shape the epigenetic landscape, underscoring the interplay between genetics and the environment in cancer etiology.
The growing significance of microRNAs and long non-coding RNAs as biomarkers for cancer detection, prognosis, and therapeutic targeting is increasingly recognized. Advances in epigenetic therapy — including epidrugs targeting DNA methyltransferases and histone-modifying enzymes — offer promising strategies for personalized cancer treatment. Plant-based miRNA therapeutic approaches may further provide cost-effective and innovative treatment options in the future.
A deeper understanding of epigenetic mechanisms has greatly advanced our grasp of cancer biology and created new opportunities for early detection, prevention, and targeted intervention. Continued research in cancer epigenetics is critical for developing more effective, less toxic treatments, ultimately improving patient outcomes and survival rates.
REFERENCES
Yoshita Pillewan, Bhavishya Jain, Dr. Musthaq Ahmed, Epigenetic Mechanisms in Human Cancers:The Role of Non-Coding RNAs and Epigenomic Reprogramming, Int. J. of Pharm. Sci., 2026, Vol 4, Issue 5, 6306-6313, https://doi.org/10.5281/zenodo.20354565
10.5281/zenodo.20354565
