Purpose: Sirtuins play an important role in cancer development. Sirt7, as a member of this family, is frequently overexpressed in certain carcinomas, but the oncogenic mechanism is seldom reported. In this study, Sirt7 was characterized for its role in colorectal cancer aggressiveness and underlying molecular mechanisms. Experimental Design: Quantitative PCR, Western blotting, and immunohistochemistry were performed to study Sirt7 expression in a cohort of colorectal cancer tissues and non-tumor tissues and cells. A series of in vitro and in vivo assays was performed to elucidate the function of Sirt7 in colorectal cancer and its underlying mechanisms. Association between the Sirt7 signature and survival was examined using Kaplan-Meier analysis and log-rank tests. Results: The Sirt7 protein level significantly correlated with tumor stage (P = 0.029), lymph node metastasis (P = 0.046), and poor patient survival (P < 0.05). Sirt7 knockdown significantly inhibited colorectal cancer cell proliferation, colony formation, and motility. Ectopic Sirt7 expression promoted colony formation, induced a more invasive phenotype, and accelerated cell growth both in vitro and in vivo. Moreover, Sirt7 enhanced MAPK pathway activity concomitantly with p-ERK and p-MEK upregulation. In Sirt7-overexpressing cells, the mesenchymal markers vimentin and fibronectin were upregulated, and the epithelial markers E-cadherin and beta-catenin were downregulated, which was linked to enhanced invasion by colorectal cancer cells. Conclusion: Our findings suggest that Sirt7 plays an important role in the development and progression of human colorectal cancer and functions as a valuable marker of colorectal cancer prognosis. (C)2014 AACR.