SETDB1 regulates microtubule dynamics

Abstract

SETDB1 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 show that a substantial cytoplasmic pool of SETDB1 is colocalized with microtubules. Significantly, silencing of SETDB1 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 affects MT dynamics by a methylation-independent mechanism. Finding interaction between SETDB1 and the tubulin deacetylase HDAC6 and increased tubulin acetylation levels upon silencing of SETDB1 suggest 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.