The protein farnesyltransferase regulates HDAC6 activity in a microtubule-dependent manner.
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.
Zhou
Jun
J
Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
Vos
Chantal Chanel
CC
Gjyrezi
Ada
A
Yoshida
Minoru
M
Khuri
Fadlo R
FR
Tamanoi
Fuyuhiko
F
Giannakakou
Paraskevi
P
D019883:Alkyl and Aryl Transferases / Q000502:physiology*; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D003593:Cytoplasm / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases / Q000502:physiology*; D006801:Humans; D008870:Microtubules / Q000378:metabolism*; D008954:Models, Biological; D017239:Paclitaxel / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D013997:Time Factors; D003986:Dibenzocycloheptenes
D019883:Alkyl and Aryl Transferases; D000972:Antineoplastic Agents, Phytogenic; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases; D017239:Paclitaxel; D010880:Piperidines; D011725:Pyridines; C064911:p21(ras) farnesyl-protein transferase; C433811:HDAC6 protein, human; C115354:lonafarnib; D003986:Dibenzocycloheptenes