Using repurposed HDAC inhibitors to promote beta-cell survival

Interferons (IFN) play an important role in the pathogenesis of type 1 diabetes (T1D). They signal via signal transducer and activator of transcription 1 (STAT1). STAT1 activity is canonically regulated by phosphorylation, however we have reported that histone deacetylase (HDAC) 6 can also control STAT1 activity by modifying STAT acetylation in beta-cells. We present preliminary data that broad-spectrum HDAC inhibitors, already in clinical use, target this pathway. Our proposal aims to assess whether these inhibitors could be repurposed as a T1D treatment. We will address this by fully characterising the impact of the clinically used broad-spectrum HDAC inhibitors, SAHA and Romidepsin, on IFN signalling in EndoC-βH1 cells and human islets; examining STAT1 phosphorylation, localisation, transcriptional activity and downstream gene/protein expression (e.g. HLA-I). To identify the HDAC isoforms responsible we will individually knockdown HDACs and examine which reciprocates the effect of the inhibitors. Expression of HDAC isoforms identified to regulate STAT1 signalling will be explored in pancreas from people with and without T1D. Finally, we will examine whether HDAC inhibitors can work additively with other putative T1D treatments which target the same pathway (JAK inhibitors). Together, these data will inform on the therapeutic potential of HDAC inhibitors as a T1D treatment.