Abstract
BackgroundThe Cdc42-interacting protein-4, Trip10 (also known as CIP4), is a multi-domain adaptor protein involved in diverse cellular processes, which functions in a tissue-specific and cell lineage-specific manner. We previously found that Trip10 is highly expressed in estrogen receptor-expressing (ER+) breast cancer cells. Estrogen receptor depletion reduced Trip10 expression by progressively increasing DNA methylation. We hypothesized that Trip10 functions as a tumor suppressor and may be involved in the malignancy of ER-negative (ER-) breast cancer. To test this hypothesis and evaluate whether Trip10 is epigenetically regulated by DNA methylation in other cancers, we evaluated DNA methylation of Trip10 in liver cancer, brain tumor, ovarian cancer, and breast cancer.MethodsWe applied methylation-specific polymerase chain reaction and bisulfite sequencing to determine the DNA methylation of Trip10 in various cancer cell lines and tumor specimens. We also overexpressed Trip10 to observe its effect on colony formation and in vivo tumorigenesis.ResultsWe found that Trip10 is hypermethylated in brain tumor and breast cancer, but hypomethylated in liver cancer. Overexpressed Trip10 was associated with endogenous Cdc42 and huntingtin in IMR-32 brain tumor cells and CP70 ovarian cancer cells. However, overexpression of Trip10 promoted colony formation in IMR-32 cells and tumorigenesis in mice inoculated with IMR-32 cells, whereas overexpressed Trip10 substantially suppressed colony formation in CP70 cells and tumorigenesis in mice inoculated with CP70 cells.ConclusionsTrip10 regulates cancer cell growth and death in a cancer type-specific manner. Differential DNA methylation of Trip10 can either promote cell survival or cell death in a cell type-dependent manner.
Highlights
The Cdc42-interacting protein-4, thyroid hormone receptor interactor 10 (Trip10), is a multi-domain adaptor protein involved in diverse cellular processes, which functions in a tissue-specific and cell lineage-specific manner
Our results show that Trip10 expression in brain tumors, breast cancer, liver cancer, and ovarian cancer is regulated by DNA methylation, but the methylation level varies among these cancer types
The Trip10 promoter was either unmethylated or undermethylated in mesenchymal stem cell (MSC) and CP70 ovarian cancer cells as revealed by bisulfite sequencing, but the same sequence was moderately methylated in breast cancer cells (MCF7 and MDA-MB231) and liver cancer cells (HepG2)
Summary
The Cdc42-interacting protein-4, Trip ( known as CIP4), is a multi-domain adaptor protein involved in diverse cellular processes, which functions in a tissue-specific and cell lineage-specific manner. Trip is a scaffold protein with F-BAR, ERM, and SH3 domains Because these domains interact with diverse signaling partners, Trip is involved in various cellular processes including insulin-stimulated glucose uptake, endocytosis, cytoskeleton arrangement, membrane invagination, proliferation, survival, and migration, in a tissuespecific and cell lineage-specific manner. Rat striatal neurons transfected with Trip exhibited increased cell death [9], suggesting that Trip is toxic to striatal neurons These data demonstrate that the function of Trip in cell survival and growth is cell lineage-specific. These diverse and sometime opposing roles of Trip may be due in part to splicing variants, but important, they could be the result of Trip interaction with distinct signaling partners in different cell types
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