Histone deacetylase 6 (HDAC6) is an emerging therapeutic target that is overexpressed in
glioblastoma when compared to other HDACs. HDAC6 catalyzes the deacetylation of
alpha-tubulin and mediates the disassembly of primary cilia, a process required for cell cycle progression. HDAC6 inhibition disrupts
glioma proliferation, but whether this effect is dependent on
tumor cell primary cilia is unknown. We found that HDAC6 inhibitors
ACY-1215 (1215) and
ACY-738 (738) inhibited the proliferation of multiple patient-derived and mouse
glioma cells. While both inhibitors triggered rapid increases in acetylated
alpha-tubulin (aaTub) in the cytosol and led to increased frequencies of primary cilia, they unexpectedly reduced the levels of aaTub in the cilia. To test whether the antiproliferative effects of HDAC6 inhibitors are dependent on
tumor cell cilia, we generated patient-derived
glioma lines devoid of cilia through depletion of ciliogenesis genes ARL13B or KIF3A. At low concentrations, 1215 or 738 did not decrease the proliferation of cilia-depleted cells. Moreover, the differentiation of
glioma cells that was induced by HDAC6 inhibition did not occur after the inhibition of cilia formation. These data suggest HDAC6 signaling at primary cilia promotes the proliferation of
glioma cells by restricting their ability to differentiate. Surprisingly, overexpressing HDAC6 did not reduce cilia length or the frequency of ciliated
glioma cells, suggesting other factors are required to control HDAC6-mediated cilia disassembly in
glioma cells. Collectively, our findings suggest that HDAC6 promotes the proliferation of
glioma cells through primary cilia.