Low dose histone deacetylase inhibitor treatment halts rhabdoid tumour growth and induces osteogenesis and neuronal differentiation.

Abstract

Rhabdoid Tumour (RT) is a rare, malignant tumour of infancy arising mainly in the kidney or CNS. RTs are highly resistant to conventional treatments and outcomes remain poor despite aggressive multimodal therapy. The sole recurrent genetic abnormality in RT is homozygous deletion or inactivation of the chromatin-remodelling gene, SMARCB1 thus providing an ideal model for exploring epigenetic therapies such as the use of histone deacetylase inhibitors (HDACi). This study investigates the effects of HDACi on cell growth and differentiation in RT cell lines and mouse xenografts and analyses resultant changes in gene expression. METHOD(S): In vitro based cell proliferation, cell cycle and colony forming assays were undertaken and the altered gene expression profiles upon HDACi treatment were analysed using Illumina expression beadchip arrays and quantitative real-time PCR. The effects of HDACi on RT cell differentiation, both in vitro and in a mouse xenograft tumour model, were determined and post-treatment, cells or tissue were stained with various differentiation markers. RESULT(S): HDACi treatment inhibited RT cell growth and self-renewal in vitro and halted tumour growth in vivo. After 21 days of continuous, low dose treatment with HDACi LBH589, gene expression signatures and qualitative differentiation marker staining of cells or tissue showed evidence of osteoblast differentiation and bone formation, as well as neuronal differentiation. CONCLUSION(S): Our data suggest that low dose HDACi treatment has the potential to inhibit RT cell growth and drive differentiation. This makes differentiation therapy an exciting avenue to explore and avoids the challenges of achieving a cytotoxic response in patients. The ability of HDACi to differentiate tumour cells and reduce their ability to self-renew warrants further investigation, as it provides an appealing means of tackling the issue of tumour recurrence.