Epigenetic Modifier Drug Valproic Acid Enhances Cancer Metaphase Chromosome Elasticity and Electron Transport: An Atomic Force Microscopy Approach.

Abstract

The structural integrity of the chromosomes is essential to every functional process within eukaryotic nuclei. Chromosomes are DNA-histone complexes that are essential for the inheritance of genetic information to the offspring, and any defect in them is linked to mitotic errors, cancer growth, and cellular aging. Changes in the mechanical properties of a chromosome could lead to its compromised function and stability, leading to chromosome breaks. Here, we studied the changes in chromosome physical properties using metaphase chromosomes isolated from moderately malignant (MCF7) and highly malignant (MDA-MB-231) human breast cancer cells exposed to valproic acid (VPA), a known epigenetic modifier drug involved in histone hyperacetylation and DNA demethylation. Due to chromosomal structural intricacy and preparative and technical limitations of analytical tools, we employed a label-free atomic force microscopy approach for simultaneously visualizing and mapping single chromosome elasticity and stretching modulus. Additionally, we performed electron transport characteristics through metaphase chromosomes to elucidate the effect of VPA. The chromosomal elasticity and electron transport alterations are manifestations of VPA-mediated chromatin's epigenetic changes. Our multiparametric strategy, as shown by receiver operating characteristics analyses with the physical properties of chromosomes, offers a new scope in terms of analytical tools for studying chromosomal structural changes/aberrations linked to cancer.