Nuclear Localization Is Not Required for Tip60 Tumor Suppressor Activity in Breast and Lung Cancer Cells

The Tip60 lysine acetyltransferase is a tumor suppressor in most cancers but an oncogene in prostate and gastric cancer. Tip60 is commonly found in the nucleus, where it acetylates proteins involved in transcription, DNA repair, and chromatin; however, it has also been shown to acetylate cytoplasmic targets. In this study, we investigated the relationship between Tip60 localization and breast and lung cancer. In cell fractionation experiments, cancer-derived cell lines showed a shift from nuclear to cytoplasmic endogenous Tip60 compared with cell lines derived from normal cells. With immunofluorescence, we observed four different localization patterns of overexpressed Tip60 and found that cancer cells had increased cytoplasmic localization of Tip60 compared with HEK-293 cells. The addition of a nuclear localization signal (NLS) increased the number of cells containing nuclear Tip60, whereas mutation of a putative endogenous NLS increased the number of cells with cytoplasmic Tip60. Overexpression of Tip60 increased cancer cell line sensitivity to paclitaxel regardless of changes in localization. These results suggest that dysregulation of Tip60 in breast and lung cancer is not limited to reduced expression but may also involve subcellular localization.