INTERNATIONAL CONGRESS OF
PharmacoGenetics
Lung Cancer Epigenetic Changes and Signalling Interactions: Mechanisms, Biomarkers, and Treatment Prospects
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shima booali,1,*
- Introduction: Introduction With a five-year survival rate of fewer than 20%, lung cancer is the primary cause of cancer-related deaths globally [1]. Oncogene and tumour suppressor gene changes have been postulated as the primary causes of lung cancer pathogenesis in recent years. However, more evidence is emerging that supports the model that epigenetic changes contribute to lung tumorigenesis, either in cooperation with genetic mutations or independently from these mutations [2,3]. Epigenetics is the study of heritable differences in gene expression that do not result from changes to the DNA sequence. Histone modifications, DNA methylation, and regulation by non-coding RNAs (ncRNAs), including long non-coding RNAs (lncRNAs) and microRNAs (miRNAs), are the three main subcategories of epigenetics [4,5]. Together, these epigenetic mechanisms alter the transcriptional state or chromatin structure, which governs not only gene expression but also cellular functions such as immune recognition evasion, differentiation, death, and proliferation. More and more reports in the literature are demonstrating that epigenetic modifications modulate and, in some cases, act as feedback regulators of important signaling pathways, including Wnt/β-catenin, PI3K/AKT/mTOR, MAPK, Notch, and TGF-β [6–8]. The connection between epigenetics and cancer-associated signalling pathways can provide valuable insights into the biology of lung cancer and potential new targets for treatment. Discussing the epigenetic mechanisms behind lung cancer, their interactions with significant oncogenic pathways, their roles as biomarkers, and their potential therapeutic benefits—including existing and planned epigenetic treatments—is the aim of this study. Epigenetic Mechanisms of Lung Cancer DNA methylation DNA methylation occurs when a methyl group is added to the 5-carbon position of cytosine inside CpG dinucleotides. When it occurs in the promoter regions of tumour suppressor genes, this would lead to transcriptional suppression of those genes. Non-small cell lung cancer (NSCLC) often exhibits hypermethylation in tumor suppressor genes (for example, CDKN2A, RASSF1A, MGMT) [9,10]. Conversely, oncogenes may be activated or genomic instability may result from global hypomethylation [11]. Histone modification Acetylation, methylation, phosphorylation, and ubiquitination are examples of post-translational modifications that can occur in histone proteins. Every modification affects chromatin structure and gene transcription. While histone deacetylases, like HDAC1 and HDAC3, are elevated and associated with poor clinical outcomes in lung cancer [12], histone methyltransferases, like EZH2, help to silence tumour suppressor genes [13]. Non-coding RNAs The post-transcriptional control of gene expression depends on non-coding RNAs, including miRNAs and lncRNAs. For instance, methylation frequently inhibits the tumour suppressor miRNA miR-34a in lung cancer [14]. LncRNAs associated with metastasis and chemoresistance include MALAT1 and HOTAIR [15]. Important Signalling Pathways and Epigenetics Interaction β-catenin and the Wnt pathway Promoter hypermethylation-based epigenetic silencing of Wnt pathway inhibitors (including SFRP1, DKK1) leads to inappropriate Wnt/β-catenin-related activation, promoting cancer cell proliferation and invasion [16,17]. AKT/mTOR/PI3K pathway This process involves several miRNAs, such as miR-21 and miR-126. When these miRNAs are dysregulated, signalling can become abnormal. The lncRNA H19 can also behave as a miRNA sponge that modulates PI3K/AKT signalling [18]. The Notch Signalling Vertical histone acetylation control governs Notch signaling pathways. Alterations in histone-modifying enzymes may result in abnormal Notch1 expression, which may induce cancer growth and treatment resistance [19]. The MAPK/ERK Pathway The action of miR-143 and miR-145 silencing MAPK/ERK signaling through targeting KRAS and other downstream effectors is an inhibitory action. The action of these microRNAs is downregulated in lung tumors, contributing to chronic signal proliferation [20]. Signalling by TGF-β Inhibitory factors of TGF-β signaling, SMAD7 for example, can undergo epigenetic silencing, and this is bound to promote epithelial to mesenchymal transition (EMT) and increased metastasis [21]. Signaling Pathway Epigenetic Modifications Involved Functional Impact in Lung Cancer Therapeutic Targeting Wnt/β-catenin Promoter methylation of antagonists (e.g., DKK1, SFRP) Promotes cell proliferation and stemness DNMT inhibitors (e.g., 5-aza-dC) Notch Histone acetylation changes; miRNA-mediated regulation Affects cell differentiation and resistance HDAC inhibitors, miRNA mimics PI3K/AKT/mTOR lncRNA-induced chromatin remodeling Enhances tumor growth and survival Epigenetic modulators combined with kinase inhibitors TGF-β Histone methylation at EMT-related genes Promotes epithelial-to-mesenchymal transition (EMT) EZH2 inhibitors NF-κB Acetylation of p65 subunit; miRNA silencing Regulates inflammation and metastasis Bromodomain inhibitors, miRNA-based therapies Lung Cancer Epigenetic Biomarkers Epigenetic indicators are increasingly being used to diagnose and prognosticate lung cancer. Two DNA methylation indicators that could be useful in the early identification of lung cancer are SHOX2 and SEPT9. Other circulating non-coding RNAs, such as miR-21, miR-210, and lncRNA GAS5, have the potential to function as non-invasive biomarkers from blood samples [22,23]. Clinical Trials and Epigenetic-Based Therapies Clinical trials are already being conducted on the application of certain epigenetic therapies. In lung cancer, some of the most studied drugs in the early phases of clinical testing include the DNMT inhibitors, azacitidine and decitabine, as well as the HDAC inhibitors, vorinostat and romidepsin [24,25]. Combinations of immune checkpoint inhibitors, targeted treatment, and epigenetic agents are being assessed in other studies [26].
- Methods: Abstract Lung cancer is an important cause of cancer deaths around the world. In addition to previously defined genetic mutations, we are beginning to recognize that key epigenetic alterations contribute to lung tumorigenesis, progression, and therapeutic resistance. Critical epigenetic mechanisms, such as DNA methylation, histone modification, and non-coding RNAs, can dynamically interact with many major cellular signaling pathways such as Wnt/β-catenin, PI3K/AKT/mTOR, Notch, MAPK/ERK, and TGF-β. These essential signalling pathways control a wide range of cellular processes, such as gene expression, invasion, proliferation, and immune evasion. In this review, we present recent advances in the study of epigenetic alterations in lung cancer and discuss how they may exchange information with signaling networks. We will then describe the impact of these pathways as diagnostic and prognostic biomarkers and describe novel epigenetic strategies being examined for therapy. The work to decipher these complex and multi-dimensionally interacting networks will eventually contribute to better targeted epigenetic combination therapies in lung cancer
- Results: Discussion The complex interactions of epigenetic processes and lung cancer oncogenic signaling pathways form a cancer burden regulatory network of high depth. Unlike terminally relinquished genetic alterations, epigenetic changes possess flexibility, making them appealing prospects for treatment. Pharmacological therapies may help restore the expression of suppressed tumor-suppressing genes, which could enhance the benefits of current treatments. Furthermore, epigenetic markers could aid in early diagnosis and increase prognosis accuracy. Despite all the possibilities, many difficulties remain. The current approaches to dealing with the consequences of certain methods of treatment directed towards the level of controlled epigenetic processes are not sufficiently accurate and reliable, raising the risk of untargeted damage. Structural differences within types of lung cancer significantly complicate the patient areas, making the use of individual epigenetic markers mandatory for customizing treatment. The development of strong, reliable, and discerning markers must be accelerated alongside the optimized method of combining through controlled epigenetic processes if real clinical benefits are to be gained.
- Conclusion: Conclusion Lung cancer pathogenesis is based on epigenetic modifications that interact with biochemical pathways that cause cancer. Gaining insight into the finer points of these processes raises the sophistication of tumour biology and opens the door to customised treatment approaches. Shifting focus from basic to applied epigenetics may transform clinical care for lung cancer patients by reshaping lung cancer detection, outcome prediction, and treatment strategies.
- Keywords: Keywords: Lung cancer, epigenetics, histone modification, non-coding RNA, signaling pathways, bioma
