Abstract
The cytoplasmic deacetylase HDAC6 is an important regulator of cellular pathways that include response to stress, protein folding, microtubule stability, and cell migration, thus representing an attractive target for cancer chemotherapy. However, little is known about its upstream regulation. Our previous work has implicated HDAC6 as a new protein target for the farnesyltransferase inhibitors (FTIs), although HDAC6 lacks a farnesylation motif. Here we show that the protein farnesyltransferase (FTase) and HDAC6 are present in a protein complex together with microtubules in vivo and in vitro. FTase binds microtubules directly via its alpha subunit, and this association requires the C terminus of tubulin. Treatment with an FTI removed FTase, but not HDAC6, from the protein complex, suggesting that the active form of FTase is bound to microtubules. Importantly, the removal of FTase from microtubules abrogated HDAC6 activity, as did a stable knockdown of the alpha subunit of FTase (FTalphaKD). Interestingly, the FTalphaKD cells showed increased sensitivity to the antiproliferative effects of Taxol and the FTI lonafarnib when used either as single agents or in combination as compared with parental cells. Altogether, these data suggest that FTase, via its tubulin-association, is a critical upstream regulator of HDAC6 activity and that FTase expression could help stratify cancer patients that would most benefit from this treatment.
Highlights
FTase is an ␣ heterodimer in which the ␣ subunit is shared with another prenylation enzyme, the geranylgeranyltransferase I, whereas the  subunit is responsible for substrate specificity
HDAC6 Interacts with FTase—We have previously shown that farnesyltransferase inhibitors (FTIs) increased tubulin acetylation and microtubule stability by inactivating the tubulin deacetylase HDAC6
Despite the wealth of new emerging data on cellular targets and pathways regulated by HDAC6, very little is known about the upstream factors that modulate HDAC6 activity per se [19, 20]
Summary
FTase is an ␣ heterodimer in which the ␣ subunit is shared with another prenylation enzyme, the geranylgeranyltransferase I, whereas the  subunit is responsible for substrate specificity (for a review, see Ref. 1). We treated A549 cells with different classes of FTIs, using concentrations that effectively inhibited the enzymatic activity of FTase, as evidenced by the inhibition of HDJ-2 farnesylation, and observed that drug treatment inhibited the HDAC6-FTase as well as the FTase-microtubule interactions, whereas it had no effect on the HDAC6-tubulin association.
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