Melatonin decreases androgen-sensitive prostate cancer growth by suppressing SENP1 expression.

BACKGROUND: Melatonin is a hormone naturally produced by the pineal gland in the brain. In addition to modulating circadian rhythms, it has pleiotropic biological effects including antioxidant, immunomodulatory, and anti-cancer effects. Herein, we report that melatonin has the ability to decrease the growth and metastasis of androgen-dependent prostate cancer. METHODS: To evaluate the anti-cancer effect of melatonin on androgen-sensitive prostate cancer in vitro or in vivo, the effects of cell proliferation, apoptosis, migration and invasion were analyzed by using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), colony formation, flow cytometry, Transwell assay, and immunohistochemistry (IHC), respectively. Next, the interaction between androgen receptor (AR) and SUMO specific protease 1 (SENP1) was detected by real-time quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and western blotting, and confirmed by luciferase reporter assay. Furthermore, the Small Ubiquitin-like Modifier (SUMO) proteins are a group of small proteins that are covalently attached to and detached from other proteins in cells to modify their function. (SUMOylation) of histone deacetylases 1 (HDAC1) was measured by proximity ligation assay (PLA). RESULTS: The treatment of melatonin cripples the transcriptional activity of AR, which is essential for the growth of the androgen-dependent prostate cancer cell, LNCaP. The lower activity of AR was dependent on melatonin induced SUMOylation of HDAC1, which has been established as a key factor for the transcriptional activity of AR. Mechanistically, the effect of melatonin on AR was due to the decreased SENP1 protein level and the subsequent increased HDAC1 SUMOylation level. The overexpression of SENP1 abrogated the anti-cancer ability of melatonin on LNCaP cells. CONCLUSIONS: These findings indicate that melatonin is a suppressor of androgen-dependent prostate cancer tumorigenesis.

Role of the SENP1-SIRT1 pathway in hyperoxia-induced alveolar epithelial cell injury.

Bronchopulmonary dysplasia (BPD) is a common complication in preterm infants, and its main pathogenesis partly involves oxidative stress. A large number of studies have shown that silent information regulator 1 (SIRT1) plays a protective role in oxidative stress. SUMO-specific protease 1 (SENP1) is vital in the nucleoplasmic distribution of SIRT1 under stress. However, whether the SENP1-SIRT1 pathway is involved in the hyperoxic lung injury is unknown. Therefore, this study aimed to explore the role and related mechanisms of the SENP1-SIRT1 pathway in hyperoxic lung injury. Peripheral blood mononuclear cells (PBMCs) from infants with BPD and SENP1-silenced alveolar epithelial cells were used as research models. PBMCs were isolated from the peripheral blood of premature infants. Next, the SENP1-silenced human alveolar epithelial cells were used to verify the role of the SENP1-SIRT1 pathway in vitro. The results indicated that the ROS level and the mRNA and protein expression of SENP1 increased in PBMCs of infants with BPD, but the expression of SIRT1 decreased in the nucleus and increased in the cytoplasm, and then the expression of acetyl-p53 (Ac-p53) increased. In the hyperoxic alveolar epithelial cell injury model, it seemed that hyperoxia could induce the same variation trend in the SENP1-SIRT1 pathway as in infants with BPD and then increased the expression of Ac-p53 and BAX, and cell apoptosis. Furthermore, silencing SENP1 could alleviate these hyperoxia-induced changes. These results suggested that SENP1 played an important role in hyperoxia-induced lung injury. It could regulate the expression and nucleoplasmic distribution of SIRT1 to inhibit its deacetylase activity, and then promoted cell apoptosis. Hence, SENP1 may become a potential intervention target of BPD in the future.

Plasma Exosome-Derived Sentrin SUMO-Specific Protease 1: A Prognostic Biomarker in Patients With Osteosarcoma.

BACKGROUND: The exosomes contain many important proteins that can be used for early tumor diagnosis or patient prognosis analysis. In this study, we investigated plasma exosome-derived sentrin SUMO-specific protease 1 (SENP1) levels as a prognostic biomarker in patients with osteosarcoma. METHODS: The expression of SENP1 protein in osteosarcoma tissues and adjacent tissues was detected by immunohistochemistry (IHC). The exosomes were identified by transmission electron microscopy, nanoparticle tracking analysis, and western blotting. ELISA was used to detect plasma exosome-derived SENP1 levels to assess prognosis in patients with osteosarcoma. RESULTS: IHC showed that the positive expression rate of SENP1 in osteosarcoma tissues was 88.33%, whereas that in adjacent tissues was 46.67% (P < 0.05). Plasma exosome-derived SENP1 levels were related to tumor size, tumor location, necrosis rate, pulmonary metastasis, and surgical stage. Both disease-free survival (DFS) and overall survival (OS) were worse in patients who had higher plasma exosome-derived SENP1 levels compared with those in patients with lower plasma exosome-derived SENP1 levels (P < 0.001). The area under the receiver operating characteristic curve (AUROC) of plasma exosome-derived SENP1, as 1-year DFS and 3-year DFS prognostic biomarkers, was 0.90 (95% CI: 0.83-0.98) and 0.96 (95% CI: 0.94-0.99), respectively. As to OS, the AUROC of plasma exosome-derived SENP1 for 1-year and 3-year prediction was 0.90 (95% CI: 0.82-0.99) and 0.96 (0.93-0.98), respectively. The plasma exosome-derived SENP1 was better than plasma SENP1 as a prognostic biomarker both in DFS and OS. CONCLUSIONS: Our findings show that the plasma exosome-derived SENP1 may serve as a novel and independent prognostic predictor in clinical applications.

Induction of SENP1 in myocardium contributes to abnormities of mitochondria and cardiomyopathy.

Defect in mitochondrial biogenesis and cardiac energy metabolism is a critical contributing factor to cardiac hypertrophy and heart failure. Sentrin/SUMO specific protease 1 (SENP1) mediated regulation of PGC-1α transcriptional activity plays an essential role in mitochondrial biogenesis and mitochondrial function. However, whether SENP1 plays a role in cardiac hypertrophy and failure is unknown. We investigated whether alteration in SENP1 expression affects cardiomyopathy and the underlying mechanism. In our present study, we found that the expression of SENP1 was induced in mouse and human failing hearts associated with induced expression of mitochondrial genes. SENP1 expression in cardiomyocytes was induced by hypertrophic stimuli through calcium/calcineurin-NFAT3. SENP1 regulated mitochondrial gene expression by de-SUMOylation of MEF-2C, which enhanced MEF-2C-mediated PGC-1α transcription. Genetic induction of SENP1 led to mitochondrial dysregulation and cardiac dysfunction in vivo. Our data showed that pathogenesis of cardiomyopathy is attributed by SENP1 mediated regulation of mitochondrial abnormities. SENP1 up-regulation in diseased heart is mediated via calcineurin-NFAT/MEF2C-PGC-1α pathway.