USP28 Deficiency Promotes Breast and Liver Carcinogenesis as well as Tumor Angiogenesis in a HIF-independent Manner

Abstract

Recent studies suggest that the ubiquitin-specific protease USP28 plays an important role in cellular repair and tissue remodeling, which implies that it has a direct role in carcinogenesis. The carcinogenic potential of USP28 was investigated in a comprehensive manner using patients, animal models, and cell culture. The findings demonstrate that overexpression of USP28 correlates with a better survival in patients with invasive ductal breast carcinoma. Mouse xenograft experiments with USP28-deficient breast cancer cells also support this view. Furthermore, lack of USP28 promotes a more malignant state of breast cancer cells, indicated by an epithelial-to-mesenchymal (EMT) transition, elevated proliferation, migration, and angiogenesis as well as a decreased adhesion. In addition to breast cancer, lack of USP28 in mice promoted an earlier onset and a more severe tumor formation in a chemical-induced liver cancer model. Mechanistically, the angio- and carcinogenic processes driven by the lack of USP28 appeared to be independent of HIF-1α, p53, and 53BP1. The findings of this study are not limited to one particular type of cancer but are rather applicable for carcinogenesis in a more general manner. The obtained data support the view that USP28 is involved in tumor suppression and has the potential to be a prognostic marker..

Transcriptomic and Proteomic analysis of clear cell foci (CCF) in the human non-cirrhotic liver identifies several differentially expressed genes and proteins with functions in cancer cell biology and glycogen metabolism

“…In particular, lack of USP28 results in an earlier onset and greater tumor burden in a mouse model of chemically (diethylnitrosamine (DEN)) induced hepatocellular carcinoma [31]. The same study also reports that USP28 expression is reduced in patients with hepatocellular carcinoma when comparing carcinoma with control liver tissue of the same patient [31] in line with the data from the current study. Functions of USP28 in different cancer cell types reveal a variety of cancer-relevant effects of USP28: it elicits stem-cell-like characteristics through LSD1-stabilization [46], it acts on p53 and GATA4 affecting cellular senescence [49], it impacts on cell proliferation through deubiquination of histone H2A [47], and it sensitizes cells to DNA-damage via its interactions with 53BP1 and claspin [44].…”

“…Knockout of Usp28 in mice promotes liver carcinogenesis in diethylnitrosamine (DEN)injected mice. Although the mechanism was supposed to involve p53 through 53BP1 [28][29][30] no major impact for this regulatory axis was found in the DEN-induced HCC`s of Usp28-KO mice [31]. As USP28 levels were downregulated in the CCF it could mediate its effects at least partially via glycogen regulation.…”

“…Known target proteins of USP28 are 53BP1 [28][29][30] and claspin [44], MYC [45], LSD1 [46] histone H2A [47] and HIF-1alpha [48]. In particular, lack of USP28 results in an earlier onset and greater tumor burden in a mouse model of chemically (diethylnitrosamine (DEN)) induced hepatocellular carcinoma [31]. The same study also reports that USP28 expression is reduced in patients with hepatocellular carcinoma when comparing carcinoma with control liver tissue of the same patient [31] in line with the data from the current study.…”

“…All animal procedures were done in accordance with Duke University Institutional Animal Care and Use Committee-approved guidelines. Sections of Usp28-KO mice were prepared as described [31].…”

Transcriptomic and Proteomic Analysis of Clear Cell Foci (CCF) in the Human Non-Cirrhotic Liver Identifies Several Differentially Expressed Genes and Proteins with Functions in Cancer Cell Biology and Glycogen Metabolism

“…Knockout of Usp28 in mice promotes liver carcinogenesis in diethylnitrosamine (DEN)-injected mice. Although the mechanism has been reported to involve p53 through 53BP1 [ 44 , 45 , 46 ], no major impact for this regulatory axis was found in the DEN-induced HCCs of Usp28 -KO mice [ 25 ]. As USP28 levels were downregulated in the CCF, it could mediate its effects at least partially via glycogen regulation.…”