Global histone modification patterns correlate with tumor phenotypes and prognostic factors in multiple tumor types. Recent studies suggest that aberrant histone modifications play an important role in cancer. However, the effects of global epigenetic rearrangements on cell functions remain poorly understood. In this study, we show that the histone H3 lysine 9 (H3K9) methyltransferase SUV39H1 is clearly involved in regulating cell migration in vitro. Overexpression of wild-type SUV39H1, but not enzymatically inactive SUV39H1, activated migration in breast and colorectal cancer cells. Inversely, migration was reduced by knockdown of SUV39H1 or chemical inhibition by chaetocin. In addition, H3K9 trimethylation (H3K9me3) was specifically increased in invasive regions of colorectal cancer tissues. Moreover, the presence of H3K9me3 positively correlated with lymph node metastasis in colorectal cancer patients. Furthermore, overexpression of SUV39H1 drove tumorigenesis in mouse, resulting in a considerable decrease in survival rate. These data indicate that H3K9 trimethylation plays an important role in human colorectal cancer progression, possibly by promoting collective cell invasion. (Cancer Sci 2013; 104: 889-895) G lobal changes in the epigenetic landscape are a hallmark of cancer.(1,2) For example, genome-wide loss of lysine 16 acetylation and lysine 20 trimethylation of histone H4 (H4K16ac and H4K20me3, respectively) is observed in multiple types of human cancers. (3,4) Moreover, global histone modification patterns predict clinical outcome, and correlate with tumor phenotypes and prognostic factors, in tumors including breast, prostate, lung, and gastric cancer.(5-10) Although somatic mutation is widely accepted as the origin of cancer, recent studies suggest that epigenetic alterations may be key initiating events, and that genetic and epigenetic alterations interact at all stages of cancer development and cancer progression. (11,12) Importantly, epigenetic aberrations, unlike genetic mutations, are potentially reversible and can potentially be restored to their normal state by epigenetic therapy. (13,14)