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PSP94, an upstream signaling mediator of prostasin found highly elevated in ovarian cancer.

ABSTRACT: Ovarian cancer is a leading cause of cancer death as diagnosis is frequently delayed to an advanced stage. Effective biomarkers and screening strategies for early detection are urgently needed. In the current study, we identify PSP94 as a key upstream factor in mediating prostasin (a protein previously reported to be overexpressed in ovarian cancer) signaling that regulates prostasin expression and action in ovarian cancer cells. PSP94 is overexpressed in ovarian cancer cell lines and patients, and is significantly correlated with prostasin levels. Signaling pathway analysis demonstrated that both PSP94 and prostasin, as potential upstream regulators of the Lin28b/Let-7 pathway, regulate Lin28b and its downstream partner Let-7 in ovarian cancer cells. Expression of PSP94 and prostasin show a strong correlation with the expression levels of Lin28b/Let-7 in ovarian cancer patients. Thus, PSP94/prostasin axis appears to be linked to the Lin28b/Let-7 loop, a well-known signaling mechanism in oncogenesis in general that is also altered in ovarian cancer. The findings suggest that PSP94 and PSP94/prostasin axis are key factors and potential therapeutic targets or early biomarkers for ovarian cancer.

SUBMITTER: Ma JX

PROVIDER: S-EPMC4540204 | biostudies-literature | 2014 Sep

REPOSITORIES: biostudies-literature

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PSP94, an upstream signaling mediator of prostasin found highly elevated in ovarian cancer.

Ma J-x JX Yan B-x BX Zhang J J Jiang B-H BH Guo Y Y Riedel H H Mueller M D MD Remick S C SC Yu J J JJ

Cell death & disease 20140904

Ovarian cancer is a leading cause of cancer death as diagnosis is frequently delayed to an advanced stage. Effective biomarkers and screening strategies for early detection are urgently needed. In the current study, we identify PSP94 as a key upstream factor in mediating prostasin (a protein previously reported to be overexpressed in ovarian cancer) signaling that regulates prostasin expression and action in ovarian cancer cells. PSP94 is overexpressed in ovarian cancer cell lines and patients, ...[more]

PMID: 25188517

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Project description:The proteasome inhibitor MG132 had been shown to prevent galactose induction of the S. cerevisiae GAL1 gene, demonstrating that ubiquitin proteasome-dependent degradation of transcription factors plays an important role in the regulation of gene expression. The deletion of the gene encoding the F-box protein Mdm30 had been reported to stabilize the transcriptional activator Gal4 under inducing conditions and to lead to defects in galactose utilization, suggesting that recycling of Gal4 is required for its function. Subsequently, however, it was argued that Gal4 remains stably bound to the enhancer under inducing conditions, suggesting that proteolytic turnover of Gal4 might not be required for its function. We have performed an alanine-scanning mutagenesis of ubiquitin and isolated a galactose utilization-defective ubiquitin mutant. We have used it for an unbiased suppressor screen and identified the inhibitor Gal80 as a suppressor of the transcriptional defects of the ubiquitin mutant, indicating that the protein degradation of the inhibitor Gal80, and not of the activator Gal4, is required for galactose induction of the GAL genes. We also show that in the absence of Gal80, Mdm30 is not required for Gal4 function, strongly supporting this hypothesis. Furthermore, we have found that Mediator controls the galactose-induced protein degradation of Gal80, which places Mediator genetically upstream of the activator Gal4. Mediator had originally been isolated by its ability to respond to transcriptional activators, and here we have discovered a leading role for Mediator in the process of transcription. The protein kinase Snf1 senses the inducing conditions and transduces the signal to Mediator, which initiates the degradation of the inhibitor Gal80 with the help of the E3 ubiquitin ligase SCF(Mdm30). The ability of Mediator to control the protein degradation of transcriptional inhibitors indicates that Mediator is actually able to direct its own recruitment to gene promoters.

Project description:Clinical trials where cancer patients were treated with protease inhibitors have suggested that the serine protease, prostasin, may act as a tumour suppressor. Prostasin is proteolytically activated by the serine protease, matriptase, which has a very high oncogenic potential. Prostasin is inhibited by protease nexin-1 (PN-1) and the two isoforms encoded by the mRNA splice variants of hepatocyte growth factor activator inhibitor-1 (HAI-1), HAI-1A, and HAI-1B.Using quantitative RT-PCR, we have determined the mRNA levels for prostasin and PN-1 in colorectal cancer tissue (n = 116), severe dysplasia (n = 13), mild/moderate dysplasia (n = 93), and in normal tissue from the same individuals. In addition, corresponding tissues were examined from healthy volunteers (n = 23). A part of the cohort was further analysed for the mRNA levels of the two variants of HAI-1, here denoted HAI-1A and HAI-1B. mRNA levels were normalised to beta-actin. Immunohistochemical analysis of prostasin and HAI-1 was performed on normal and cancer tissue.The mRNA level of prostasin was slightly but significantly decreased in both mild/moderate dysplasia (p < 0.001) and severe dysplasia (p < 0.01) and in carcinomas (p < 0.05) compared to normal tissue from the same individual. The mRNA level of PN-1 was more that two-fold elevated in colorectal cancer tissue as compared to healthy individuals (p < 0.001) and elevated in both mild/moderate dysplasia (p < 0.01), severe dysplasia (p < 0.05) and in colorectal cancer tissue (p < 0.001) as compared to normal tissue from the same individual. The mRNA levels of HAI-1A and HAI-1B mRNAs showed the same patterns of expression. Immunohistochemistry showed that prostasin is located mainly on the apical plasma membrane in normal colorectal tissue. A large variation was found in the degree of polarization of prostasin in colorectal cancer tissue.These results show that the mRNA level of PN-1 is significantly elevated in colorectal cancer tissue. Future studies are required to clarify whether down-regulation of prostasin activity via up regulation of PN-1 is causing the malignant progression or if it is a consequence of it.

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PSP94, an upstream signaling mediator of prostasin found highly elevated in ovarian cancer.

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PSP94, an upstream signaling mediator of prostasin found highly elevated in ovarian cancer.

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