Deletion and mutation of PTEN are frequent in human cancers. These alterations disturb PI3K signaling and increase survival of cancer cells. Here, we report a pro-cancer growth Pten-NOLC1 gene fusion originated from a chr10 rearrangement. Expressed as a nuclear chimera protein, Pten-NOLC1 interacts with the promoter regions of genes like EGFR, c-MET and GAB1 and promotes cancer cell growth, invasion, and increases survivals; and increases metastasis and mortality in vivo. Pten-NOLC1 fusion is detected in primary human cancer samples and cancer cell lines from different organs. Genomic interruption of Pten-NOLC1 induces large number of cancer cell death. Genome integration of this fusion gene coupled with somatic Pten deletion produces liver cancer in mice. Our studies show that genome rearrangement of Pten-NOLC1 is functional. The nuclear interaction of Pten-NOLC1 drives cancer growth, and disruption of this fusion gene may be a potential target in the treatment of human cancers.