Abstract 4722: Chronic upregulation of glucocorticoid hormones triggers chromatin remodeling in NSCLC through dynamic regulation of histone H3 chaperones

Abstract

Abstract Lung cancer is the most common cause of cancer death worldwide, with a five-year survival rate of only 18.6%. Aging is a well-established risk factor for lung cancer development. However, our understanding of how the aging process affects lung cancer remains cripplingly small. In this study, we aim to bridge this gap by evaluating the effects of glucocorticoid hormones (e.g. cortisol), which become chronically upregulated during the aging process, in lung cancer cells. Phenotypically, our studies revealed that chronic exposure to age-related levels of cortisol trigger a mesenchymal-like senescent state in lung cancer cells that favors motility and invasiveness. Acquisition of pro-aggressive features are generally recognized to be driven by epigenetic regulation. Epigenetic regulation occurs at several levels, but perhaps one of the most fundamental levels is nucleosome remodeling via histone variants and their cognate chaperones. Histone H3 variants are critical regulators of nucleosome stability and have a highly specialized histone chaperone network when compared to other histones. Strikingly, we observed that chronic exposure of lung cancer cells to cortisol leads to a pronounced decline in canonical histone levels, which was accompanied by a 40% increase in chromatin accessibility genome-wide. Chromatin accessibility by transcriptional machinery is heavily influenced by histone variants, thus, we hypothesized that cortisol also regulates deposition of histone H3 variants into chromatin. The CAF-1 complex deposits the canonical H3 variants (H3.1/H3.2) onto DNA in a cell-cycle-dependent manner while other histone chaperones, HIRA at genic and DAXX at telomeric regions, deposit the H3.3 variant independently of cell cycle. In accordance with the decline in canonical histone levels, treatment with cortisol suppressed the expression of the CAF-1 complex. Reduced canonical histone abundance is known to trigger “gap filling” of naked DNA with the H3.3 variant to maintain integrity. In support of the idea that H3.3 becomes enriched in chromatin upon chronic exposure of lung cancer cells to cortisol, our results showed that the proportion of H3.3 increases upon cortisol exposure, and concomitantly H3.3 chaperone HIRA is induced upon treatment with cortisol. These data support a model in which chronic exposure to glucocorticoids, as it occurs with aging or through treatment with synthetic glucocorticoids (e.g. dexamethasone), regulates nucleosome abundance and composition in lung cancer cells through dynamic regulation of histone H3 chaperone systems. Together, we propose that this glucocorticoid-induced nucleosome remodeling establishes a chromatin environment that enables the transition to a mesenchymal-like senescent state in lung cancer cells that favors aggressiveness and poor prognosis. Citation Format: Benito M. Traversa, Devesh Raizada, Eva Kragelj, Julia Spegel, Didem Ilter, Ana P. Gomes. Chronic upregulation of glucocorticoid hormones triggers chromatin remodeling in NSCLC through dynamic regulation of histone H3 chaperones. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4722.