Pharmacologically induced proteolysis of histone deacetylase-6 attenuates influenza virus replication despite limited anti-tumor effects

Abstract

The protein deacetylase HDAC6 has been controversially linked to cancer cell proliferation and viral propagation. We analyzed whether a pharmacological depletion of HDAC6 with a recent proteolysis-targeting chimera (PROTAC) kills tumor cells. We show that low micromolar doses of the cereblon-based PROTAC TH170, but not its inactive analog TH170E, induce proteasomal degradation of HDAC6. The elimination of HDAC6 by TH170 does not compromise leukemia cell growth and survival, DNA integrity, and the stability of selected cancer-relevant proteins. Increasing the doses of TH170 generates a hook-effect on HDAC6 degradation and the apoptosis-associated fragmentation of HDAC6. Unlike the specific elimination of HDAC6 that low doses of TH170 evoke, this fragmentation of HDAC6 is linked to apoptosis and an accumulation of acetylated histones. Thus, like HDAC6 inhibitors, pharmacological degraders of HDAC6 do not induce leukemic cell death unless they are used in non-selective concentrations. Bioinformatic analyses of 91 lymphoid, 37 myeloid, and 125 lung cancer cells in which HDAC6 was deleted by CRISPR-Cas9 corroborate these data. HDAC6 is expressed in various bronchus and lung cell types. In a human lung cell model, TH170 reduces influenza A virus replication dependent on the strain and without compromising cell vitality. These data suggest that pharmacologically amenable kinase-independent functions of HDAC6 control viral replication. Eliminating HDAC6 could be a promising anti-viral strategy with a benign impact on host cells.