A histone deacetylase-dependent screen in yeast

Histone deacetylase (HDAC) proteins are promising targets for cancer treatment, as shown by the recent FDA approval of the HDAC inhibitor suberoylanilide hydroxamic acid (SAHA, Vorinostat) for the treatment of cutaneous T-cell lymphoma. To identify additional potent inhibitors and characterize HDAC mutant proteins, there is interest to develop an inexpensive screening method dependent on native substrates. Here, we report the first yeast-based gene reporter screen dependent on the yeast Rpd3, which is a homolog of human class I HDAC proteins. The screen was sensitive to an inactive Rpd3 mutant and various inhibitors in qualitative, agar-based and quantitative, solution-phase formats. Interestingly, inclusion of the lytic enzyme zymolyase enhanced the inhibitor sensitivity of the screen. The gene reporter screen provides a tool to screen Rpd3 mutants and inhibitors of class I HDAC proteins.