A69

HR23B: a biomarker for histone deacetylase inhibitor treatment in cutaneous T cell lymphoma

Omar Khan, Susan Fotheringham, Lindsay Stimson, Victoria Wood, Mark Middleton, Nick La Thangue

University of Oxford, UK

Background

The histone deacetylase HDAC inhibitor (HDI), vorinostat, has been approved for use by the FDA in advanced cutaneous T-cell lymphoma (CTCL). HDIs cause tumour cells to undergo apoptosis and several clinical trials are ongoing investigating these agents in a wide range of tumour types. A genome-wide loss-of-function screen identified HR23B, which shuttles ubiquitinated cargo proteins to the proteasome, as a sensitivity determinant for HDI-induced apoptosis. Aberrant proteasome activity may contribute to the anti-cancer activity of HDIs. The aim of this study was to determine the role of HR23B in CTCL.

Method

Sensitivity of CTCL cells to increasing concentrations of several HDAC inhibitors and bortezomib was analysed and the importance of HR23B in cellular sensitivity to HDIs and bortezomib was determined. The ability of HDIs to inhibit the proteasome was investigated.

Results

HR23B expression in CTCL cell lines increased when treated with low doses of HDI and bortezomib and decreased with higher doses. HR23B was shown to be important in cellular sensitivity to HDI as HR23B shRNA in CTCL cells reduced the ability of the cells to undergo apoptosis. HDI treatment resulted in inhibition of proteasome activity.

Conclusion

HR23B regulates the sensitivity of CTCL cell lines to HDI-induced apoptosis. Impairment of proteasome function in cells treated with HDI is mediated via HR23B. Future studies will focus on studying HR23B in tumour biopsies and assessing its role as an informative biomarker.