Epigenetics of Most Aggressive Solid Tumors: Pathways, Targets and Treatments

Abstract

Highly aggressive tumors are characterized by a highly invasive phenotype, and they display chemoresistance. Furthermore, some of the tumors lack expression of biomarkers for target therapies. This is the case of small-cell lung cancer, triple-negative breast cancer, pancreatic ductal adenocarcinoma, glioblastoma, metastatic melanoma, and advanced ovarian cancer. Unfortunately, these patients show a low survival rate and most of the available drugs are ineffective. In this context, epigenetic modifications have emerged to provide the causes and potential treatments for such types of tumors. Methylation and hydroxymethylation of DNA, and histone modifications, are the most common targets of epigenetic therapy, to influence gene expression without altering the DNA sequence. These modifications could impact both oncogenes and tumor suppressor factors, which influence several molecular pathways such as epithelial-to-mesenchymal transition, WNT/β–catenin, PI3K–mTOR, MAPK, or mismatch repair machinery. However, epigenetic changes are inducible and reversible events that could be influenced by some environmental conditions, such as UV exposure, smoking habit, or diet. Changes in DNA methylation status and/or histone modification, such as acetylation, methylation or phosphorylation, among others, are the most important targets for epigenetic cancer therapy. Therefore, the present review aims to compile the basic information of epigenetic modifications, pathways and factors, and provide a rationale for the research and treatment of highly aggressive tumors with epigenetic drugs.

Interrogating Epigenome toward Personalized Approach in Cutaneous Melanoma

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DNA methylation analysis of tumor suppressor genes in liquid biopsy components of early stage NSCLC: a promising tool for early detection

“…DNA methylation plays an essential role in regulating gene expression and modifying chromatin conformation [ 11 ]. Epigenetic biomarkers have been discovered in various types of cancer [ 12 ] since DNA methylation alterations are frequently observed and have diverse implications in carcinogenesis, diagnosis and prediction. Beyond DNA mutations, changes in DNA methylation patterns are known to arise early during cancer pathogenesis and in many cases hypermethylation in the promoter region of selected genes is thought to have carcinogenic and prognostic effects [ 13 , 14 ].…”

Emerging Role of Epigenetic Alterations as Biomarkers and Novel Targets for Treatments in Pancreatic Ductal Adenocarcinoma

“…As the epigenome is involved in several aspects of tumorigenesis, epigenetic alterations may also serve as therapeutic targets. Nonetheless, the epigenetic field is in its relative infancy, with few drugs in clinical use for treating solid tumors [13].…”