Epigenetic dynamics and molecular mechanisms in oncogenesis, tumor progression, and therapy resistance

Abstract

Cancer progression is governed by a dynamic interplay of genetic, epigenetic, and molecular mechanisms that regulate tumor initiation, growth, metastasis, and therapy resistance. This review highlights key molecular pathways involved in oncogenesis, focusing on genetic alterations (mutations, amplifications, and translocations) in oncogenes (RAS and MYC) and tumor suppressor genes (TP53 and PTEN). Additionally, genomic instability, resulting from defective DNA repair mechanisms like mismatch repair and homologous recombination (HR), is identified as a critical factor contributing to tumor heterogeneity and clonal evolution. Epigenetic modifications, including DNA methylation, histone acetylation, and non-coding RNA regulation, further remodel chromatin structure and modulate gene expression, influencing tumor initiation, growth, metastasis, and response to treatment. Post-translational modifications, such as the attachment of a Small Ubiquitin-like Modifier (SUMO) to a target protein and ubiquitination, further influence autophagy, apoptosis, and cellular plasticity, enabling cancer cells to survive therapeutic stress. Cutting-edge technologies such as CRISPR-Cas9-mediated epigenome editing and single-cell RNA sequencing have opened new doors to understanding cellular diversity and regulatory networks in cancer. The review further examines the tumor microenvironment, including stromal remodeling, immune evasion, and hypoxia-driven signaling pathways, which are critical modulators of tumor progression and drug resistance to treatment. By integrating molecular, genetic, and epigenetic perspectives, this study underscores the crucial need for innovative, targeted therapeutic approaches to address the complexity and adaptability of cancer, thereby paving the way for more effective treatments. © The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature 2025.