Discerning oncogenic drivers from passengers remains a major effort in understanding of the essence of the initiation and development of hepatocellular carcinoma (HCC), the most common primary liver malignancy and the third leading cause of cancer mortality worldwide. Here we report that MTA2, Metastasis Associated 1 Family Member 2, is significantly up-regulated in HCC. We show that high level of MTA2 expression is strongly correlated with advanced pathological stages and poor overall survival of the patients. Genome-wide identification of the transcriptional targets of MTA2 by ChIP-seg indicates that MTA2 represses a cohort of genes including FRMD6 that are critically involved in the growth and mobility of HCC. We demonstrate that the MTA2 promotes the proliferation and metastasis of HCC in vitro and in vivo through suppressing Hippo signaling pathway. Together, these results reveal a key role for the MTA2-FRDM6-Hippo axis in human hepatocarcinogenesis. (C) 2019 Elsevier Inc. All rights reserved.