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Background   P16  DNA methylation is well known to be the most frequent event in cancer development. It has been reported that genetic inactivation of  P16  drives cancer growth and metastasis, however, whether  P16  DNA methylation is truly a driver in cancer metastasis remains unknown.    Results  A  P16 -specific DNA methyltransferase ( P16-dnmt ) expression vector is designed using a  P16  promoter-specific engineered zinc finger protein fused with the catalytic domain of  dnmt3a .  P16-dnmt  transfection significantly decreases  P16  promoter activity, induces complete methylation of  P16  CpG islands, and inactivates  P16  transcription in the HEK293T cell line. The P16-Dnmt coding fragment is integrated into an expression controllable vector and used to induce  P16 -specific DNA methylation in GES-1 and BGC823 cell lines. Transwell assays show enhanced migration and invasion of these cancer cells following  P16 -specific DNA methylation. Such effects are not observed in the  P16  mutant A549 cell line. These results are confirmed using an experimental mouse pneumonic metastasis model. Moreover, enforced overexpression of  P16  in these cells reverses the migration phenotype. Increased levels of RB phosphorylation and NFκB subunit  P65  expression are also seen following  P16 -specific methylation and might further contribute to cancer metastasis.    Conclusion   P16  methylation could directly inactivate gene transcription and drive cancer metastasis.    Electronic supplementary material  The online version of this article (doi:10.1186/s13059-015-0819-6) contains supplementary material, which is available to authorized users.

P16-specific DNA methylation by engineered zinc finger methyltransferase inactivates gene transcription and promotes cancer metastasis