USP39 stabilizes ß-catenin by deubiquitination and suppressing E3 ligase TRIM26 pre-mRNA maturation to promote HCC progression.

Ubiquitin-specific protease 39(USP39) plays an important role in modulating pre-mRNA splicing and ubiquitin-proteasome dependent proteolysis as a member of conserved deubiquitylation family. Accumulating evidences prove that USP39 participates in the development of hepatocellular carcinoma (HCC). However, little is known about the mechanism especially deubiquitinating target of USP39 in regulating hepatocellular carcinoma (HCC) growth. Here, we prove that USP39 promotes HCC cell proliferation and migration by directly deubiquitin ß-catenin, a key molecular of Wnt/ß-catenin signaling pathway whose abnormal expression or activation results in several tumors, following its co-localization with USP39. In this process, the expression of E3 ligase TRIM26, which is proved to restrain HCC in our previous research, shows a decreasing trend. We further demonstrate that TRIM26 pre-mRNA splicing and maturation is inhibited by USP39, accompanied by its reduction of ubiquitinating ß-catenin, facilitating HCC progression indirectly. In summary, our data reveal a novel mechanism in the progress of HCC that USP39 promotes the proliferation and migration of HCC through increasing ß-catenin level via both direct deubiquitination and reducing TRIM26 pre-mRNA maturation and splicing, which may provide a new idea and target for clinical treatment of HCC.

USP39 attenuates the antitumor activity of cisplatin on colon cancer cells dependent on p53.

Cisplatin is the effective chemotherapeutic drug in colon cancer treatment, but its therapeutic efficacy is limited by intrinsic or acquired drug resistance and detrimental side effects. Therefore, improving the effect of cisplatin chemotherapy remains a great challenge. The previous study identified that USP39 was relevant to cisplatin resistance of lung cancer. However, the function and mechanisms of USP39 regulating the chemosensitivity of cisplatin in colorectal cancer remain unclear. In this study, we reveal that USP39 is associated with colon cancer cells sensitivity to cisplatin. Depletion of USP39 enhances the cisplatin-induced apoptosis in HCT116 cells. Conversely, overexpression of USP39 attenuates apoptosis in RKO cells. Furthermore, we demonstrate that USP39 depletion promotes apoptosis induced by cisplatin, which is related with the induction of oxidative stress and DNA damage response. Further studies show that USP39 regulates cisplatin-induced apoptosis dependent on p53. The underlying mechanism is demonstrated by knocking down USP39, that results in p53 upregulation, associated with its prolonged half-life. Collectively, our findings reveal that USP39 might be a negative factor of the p53 mediated cisplatin sensitivity of colon cancer, and suggest USP39 as a potential molecular target for cisplatin chemotherapy of colon cancer.

Protective effect and mechanism of loganin and morroniside on acute lung injury and pulmonary fibrosis.

BACKGROUND: Loganin and morroniside are two iridoid glycosides with anti-inflammatory, antioxidant and anti-tumor effects. Whether they have effect on acute lung injury and pulmonary fibrosis are still unknown. PURPOSE: To explore the potential effects of loganin and morroniside against acute lung cancer and pulmonary fibrosis, and the underlying molecular mechanism. STUDY DESIGN AND METHODS: Cell and animal models of acute lung injury were established by the induction of LPS. After intervention with loganin and morroniside, the pathological symptom of lung tissue was assessed, pro-inflammatory factors in cells and lung tissues were detected, NF- κB/STAT3 signaling pathway related proteins were detected by western blotting. Mice pulmonary fibrosis model was induced by bleomycin, pathological symptom was assessed by HE and Masson staining. Fibrosis related indicators were detected by qPCR or western blot. CD4+/CD8+ was detected by flow cytometry. RESULTS: Loganin and morroniside relieved the pathological symptom of lung tissue in acute lung injury, pro-inflammatory factors such as IL-6, IL-1ß, TNF-α mRNA were inhibited. Expression of p-p65 and STAT3 in lung tissues were also downregulated. In addition, loganin and morroniside downregulated the expression of collagen fiber, hydroxyproline and TGF-ß1, collagen I and α-SMA mRNA in lung tissues of pulmonary fibrosis model. This study proved that loganin and morroniside have protective effect on acute lung injury and pulmonary fibrosis, and may provide theoretical basis for the development of new clinical drugs.

Deubiquitinase USP39 and E3 ligase TRIM26 balance the level of ZEB1 ubiquitination and thereby determine the progression of hepatocellular carcinoma.

Emerging evidence suggests that USP39 plays an important role in the development of hepatocellular carcinoma (HCC). However, the molecular mechanism by which USP39 promotes HCC progression has not been well defined, especially regarding its putative ubiquitination function. Zinc-finger E-box-binding homeobox 1 (ZEB1) is a crucial inducer of epithelial-to-mesenchymal transition (EMT) to promote tumor proliferation and metastasis, but the regulatory mechanism of ZEB1 stability in HCC remains enigmatic. Here, we reveal that USP39 is highly expressed in human HCC tissues and correlated with poor prognosis. Moreover, USP39 depletion inhibits HCC cell proliferation and metastasis by promoting ZEB1 degradation. Intriguingly, deubiquitinase USP39 has a direct interaction with the E3 ligase TRIM26 identified by co-immunoprecipitation assays and immunofluorescence staining assays. We further demonstrate that TRIM26 is lowly expressed in human HCC tissues and inhibits HCC cell proliferation and migration. TRIM26 promotes the degradation of ZEB1 protein by ubiquitination in HCC. Deubiquitinase USP39 and E3 ligase TRIM26 function in an antagonistic pattern, but not a competitive pattern, and play key roles in controlling ZEB1 stability to determine the HCC progression. In summary, our data reveal a previously unknown mechanism that USP39 and TRIM26 balance the level of ZEB1 ubiquitination and thereby determine HCC cell proliferation and migration. This novel mechanism may provide new approaches to target treatment for inhibiting HCC development by restoring TRIM26 or suppressing USP39 expression in HCC cases with high ZEB1 protein levels.

USP39 mediates p21-dependent proliferation and neoplasia of colon cancer cells by regulating the p53/p21/CDC2/cyclin B1 axis.

Ubiquitin-specific protease 39 (USP39) is frequently overexpressed in a variety of cancers, and involved in the regulation of various biological processes, such as cell proliferation, cell cycle progression, apoptosis and pre-messenger RNA splicing. Nevertheless, the biological roles and mechanisms of USP39 in colon cancer remain largely unknown. In this study, we analyzed whether USP39 can be a molecular target for the treatment of colon cancer. Whilst overexpression of USP39 was detected in human colon cancer tissues and cell lines, USP39 knockdown was observed to inhibit the growth and subcutaneous tumor formation of colon cancer cells. Further analysis showed that USP39 knockdown can stabilize p21 by prolonging the half-life of p21 and by upregulating the promoter activity of p21. The RS domain and USP domain of USP39 were found to play an essential role. Additionally, our findings revealed that USP39 plays a regulatory role in the proliferation of colon cancer cells by the p53/p21/CDC2/cyclin B1 axis in a p21-dependent manner. Taken together, this study provided the theoretical basis that may facilitate the development of USP39 as a novel potential target of colon cancer therapy.