Effetti molecolari del Dexamethasone su cellule di pazienti con Atassia Teleangectasia

Ataxia-telangiectasia (AT) is a rare autosomal recessive disorder caused by mutations in the ataxia-telangiectasia mutated gene (ATM), which codifies for a protein kinase mainly involved in DNA damage response. No established therapy is currently available for this disease but, recently, short term treatment with Dexamethasone (Dexa) was shown to improve the symptoms of this syndrome. Nevertheless, the molecular mechanism involved in Dexa action in AT patients is not yet know. Here we examined the effects of dexamethasone treatment in human primary fibroblast ATM-/- GM02052, GM00648 and in the control cell line ATM+/+ AG09429. We observed, for the first time, a nucleoplasmic accumulation of Lamin A only in ATM muted cell lines treated with Dexa, probably induced by an increased phosphorylation in Lamin A Ser22 and Ser404. Lamin A Ser404 is a nuclear target of AKT, and Dexa resulted capable to exclusively activate AKT phosphorylation in ATM-/- GM00648 cell line, endorsing the Lamin A accumulation. Furthermore, ChIP-seq analysis revealed 457 (GM00648 cells) versus 12 (WT cells) genomic sequences for transcription factors binding to Lamin A/C, after Dexamethasone treatment. Among them, the genomic sequences for HIF-1α, ARNT and E47 transcription factors detected in GM00648 ChIP with Dexa, were also identified as possibly activated in the same cell line by TF array assay. Finally Dexamethasone treatment seemed able to increased HDAC4 reduction and consequent nuclear accumulation through a possible NRF2-mediated up regulation of tioredoxin1 (TXN) gene expression. Also an increased interaction between nuclear HDAC4 and HIF-1α appeared to be involved in Dexamethasone effect in these cell lines. Hence, Dexamethasone treatment could be involved in epigenetic modulation in AT cell lines increasing Lamin A/C and HDAC4 nuclear content and interactions.