SETDB1 regulates microtubule dynamics

ObjectivesSETDB1 is a methyltransferase responsible for the methylation of histone H3‐lysine‐9, which is mainly related to heterochromatin formation. SETDB1 is overexpressed in various cancer types and is associated with an aggressive phenotype. In agreement with its activity, it mainly exhibits a nuclear localization; however, in several cell types a cytoplasmic localization was reported. Here we looked for cytoplasmic functions of SETDB1.MethodsSETDB1 association with microtubules was detected by immunofluorescence and co‐sedimentation. Microtubule dynamics were analysed during recovery from nocodazole treatment and by tracking microtubule plus‐ends in live cells. Live cell imaging was used to study mitotic kinetics and protein–protein interaction was identified by co‐immunoprecipitation.ResultsSETDB1 co‐sedimented with microtubules and partially colocalized with microtubules. SETDB1 partial silencing led to faster polymerization and reduced rate of catastrophe events of microtubules in parallel to reduced proliferation rate and slower mitotic kinetics. Interestingly, over‐expression of either wild‐type or catalytic dead SETDB1 altered microtubule polymerization rate to the same extent, suggesting that SETDB1 may affect microtubule dynamics by a methylation‐independent mechanism. Moreover, SETDB1 co‐immunoprecipitated with HDAC6 and tubulin acetylation levels were increased upon silencing of SETDB1.ConclusionsTaken together, our study suggests a model in which SETDB1 affects microtubule dynamics by interacting with both microtubules and HDAC6 to enhance tubulin deacetylation. Overall, our results suggest a novel cytoplasmic role for SETDB1 in the regulation of microtubule dynamics.

SETDB1 association with microtubules inhibits microtubule polymerization and enhances their instability. SETDB1 may affect the microtubules by interacting with HDAC6 to enhance HDAC6 tubulin deacetylation activity.