Cytoplasmic roles of the histone methyl-transferase SETDB1

SETDB1 is a histone methyl-transferase responsible for the methylation of histone 3 on lysine 9. Its major outcome is the tri-methylation on this position, H3K9me3, which is related to gene silencing and one of the hallmarks of heterochromatin regions. SETDB1 is overexpressed in various cancer types and is thought to be associated with an aggressive phenotype. In agreement with its activity, it is mainly a nuclear protein but its cytoplasmic localization has been revealed in few studies. This subcellular localization raises the question of whether SETDB1 has an activity in this compartment of the cell. Here we show that a substantial cytoplasmic pool of SETDB1 is co-localized with microtubules in both mouse and human melanoma cells. Moreover, SETDB1 co-immunoprecipitated with the intermediate chain of dynein, which is the major minus-end directed motor protein. Silencing of SETDB1 led to increased microtubule stability as measured by acetylated tubulin levels. In agreement with that, silencing or over-expression of SETDB1 led to an increase and a decrease in microtubule polymerization rate during recovery from nocodazole treatment, respectively. Interestingly, the effect of SETDB1 on microtubule re-growth was independent of its methyl-transferase activity. Overall, our results suggest a novel cytoplasmic and methyl-transferase independent role for SETDB1 in regulating microtubule dynamics. In the long run, this study can establish a moonlight function of SETDB1 that is highly relevant to tumor progression and to reveal a possible crosstalk between nuclear chromatin dynamics and cytoplasmic microtubule functions.