Carnosine influences transcription via epigenetic regulation as demonstrated by enhanced histone acetylation of the pyruvate dehydrogenase kinase 4 promoter in glioblastoma cells

Abstract

Carnosine (β-alanyl-L-histidine) affects a plethora of signaling pathways and genes in different biological systems. Although known as a radical scavenger, not all of these effects can simply be ascribed to its chemical nature. As previous experiments pointed towards the possibility that carnosine affects epigenetic regulation via histone acetylation, we investigated this hypothesis using the glioblastoma cell lines U87 and T98G in which carnosine's anti-neoplastic effect is accompanied by increased expression of pyruvate dehydrogenase kinase 4. Viability and expression of PDK4 was analyzed after incubation in carnosine and different histone deacetylase inhibitors (HDACi) using cell-based assays and qRT-PCR. In addition, chromatin immunoprecipitation (ChIP) experiments were performed and the global influence of carnosine on histone H3 acetylation was analyzed by Western blot. Carnosine as well as the HDACi used increased expression of PDK4. In addition, all compounds reduced cell viability, although differences were observed with regard to magnitude and required concentrations. ChIP analysis revealed increased acetylation of histone H3 in the PDK4 promoter of U87 and T98G cells (~ 1.3- and ~ 1.7-fold, respectively) 6 h after the addition of carnosine (50 mM) followed by increased expression of PDK4 mRNA. Western blots did not detect a general increase of H3 acetylation at a genome-wide scale under the influence of carnosine. Our experiments for the first time demonstrate that carnosine influences epigenetic regulation via increased histone acetylation.

An update on carnosine and anserine research

“…The pleiotropic action of carnosine implies therapeutic potential in various diseases, including cancer and neurodegeneration. The contribution byOppermann et al (2019) describes a novel level of complexity by suggesting carnosine's influence on epigenetic regulation in glioblastoma cells Berezhnoy et al (2019). review the role of carnosine as a neuromodulator and neuroprotector.…”

Carnosine synthase deficiency is compatible with normal skeletal muscle and olfactory function but causes reduced olfactory sensitivity in aging mice

“…However, it is also possible that Carns1 deficiency causes increased production of reactive carbonyls or impairs degradation of carbonylated proteins. Absence of carnosine may also alter gene expression as demonstrated by its effect on histone acetylation (58,59). Whether increased protein carbonylation and loss of ORN may be secondary to altered gene expression will require further studies.…”

Important roles of dietary taurine, creatine, carnosine, anserine and 4-hydroxyproline in human nutrition and health

“…Carnosine also plays a role in the inhibition of the growth and migration but induction of apoptosis of tumor cells, including human glioblastoma cells as well as colorectal and ovarian carcinoma cells (Hipkiss and Gaunitz 2014;Hsieh et al 2019;Iovine et al 2016), as well as the suppression of the release of interleukin-6 by lipopolysaccharides plus interferon-γ-activated macrophages (Caruso et al 2017). Most recently, carnosine was reported to influence epigenetic regulation of gene expression in mammalian cells via increased histone acetylation (Oppermann et al 2019). Compared with its constituent amino acids, the formation of carnosine can reduce intracellular osmolarity in the skeletal muscle and olfactory bulb, thereby protecting their integrity and function.…”