HJURP promotes proliferation in prostate cancer cells through increasing CDKN1A degradation via the GSK3β/JNK signaling pathway.
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ABSTRACT:
SUBMITTER: Lai W
PROVIDER: S-EPMC8184824 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundHolliday junction recognition protein (HJURP) has been implicated in many cancers including hepatocellular carcinoma (HCC). However, the underlying mechanism by which HJURP promotes HCC cell proliferation remains unclear.MethodsRT-qPCR and immunohistochemistry were used to detect HJURP expression in HCC and adjacent tumor tissues and HCC cell lines. The localization of p21 were determined by immunofluorescence and western blot. Co-immunoprecipitation and western blot were used to validate the p21 stability and signaling pathways affected by HJURP. The effects of HJURP on HCC cell proliferation were assessed both in vivo and in vitro. The ERK1/2 pathway inhibitor U0126 and AKT pathway agonist SC-79 were used to treat HCC cell lines for further mechanistic investigations.ResultsHJURP expression was higher in HCC tissues than in para-tumor tissues. Moreover, ectopic HJURP expression facilitated the proliferation of HCC cells, whereas the depletion of HJURP resulted in decreased cell growth in vitro and in vivo. Furthermore, the effects of HJURP silencing were reversed by p21 knockdown. Likewise, p21 overexpression inhibited cell growth ability mediated by HJURP elevation. Mechanistically, HJURP destabilized p21 via the MAPK/ERK1/2 and AKT/GSK3β pathways, which regulated the nucleus-cytoplasm translocation and ubiquitin-mediated degradation of p21. Clinically, high HJURP expression was correlated with unfavorable prognoses in HCC individuals.ConclusionsOur data revealed that HJURP is an oncogene that drives cell cycle progression upstream of p21 in HCC. These findings may provide a potential therapeutic and prognostic target for HCC.
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Project description:Peptidylarginine deiminase 4 (PAD4), a Ca2+-dependent enzyme, catalyzes the conversion of arginine to citrulline and has been strongly associated with many malignant tumors. However, the molecular mechanisms of PAD4 in the development and progression of colorectal cancer (CRC) remain unclearly defined. In our study, PAD4 expression was increased in CRC tissues and cells, and was closely related to tumor size, lymph node metastasis. Moreover, the transcription factor KLF9 directly bound to PADI4 gene promoter, leading to overexpression of PAD4 in CRC cells, which augmented cell growth and migration. We revealed that PAD4 interacted with and citrullinated glycogen synthase kinase-3β (GSK3β) in CRC cells, and GSK3β Arg-344 was the dominating PAD4-citrullination site. Furthermore, IgL2 and catalytic domains of PAD4 directly bound to the kinase domain of GSK3β in CRC cells. Mechanistically, PAD4 promoted the transport of GSK3β from the cytoplasm to the nucleus, thereby increasing the ubiquitin-dependent proteasome degradation of nuclear cyclin-dependent kinase inhibitor 1 (CDKN1A). Our study is the first to reveal the details of a critical PAD4/GSK3β/CDKN1A signaling axis for CRC progression, and provides evidence that PAD4 is a potential diagnosis biomarker and therapeutic target in CRC.
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Project description:Breast cancer is the most common malignancy among women. Inorganic pyrophosphatase 1 (PPA1) is a multifunctional protein involved in the development of several tumors. However, the role of PPA1 in breast cancer progression remains unclear. In this study, we found that PPA1 was highly expressed in breast cancer compared to its levels in normal breast tissue and that it was correlated with breast cancer clinicopathological characteristics, as well as poor survival in breast cancer patients. Silencing PPA1 restrained breast cancer proliferation and metastasis by regulating Slug-mediated epithelial-mesenchymal transition (EMT). Opposite results were observed following PPA1 overexpression. In addition, investigation of the underlying mechanism demonstrated that PPA1 ablation led to decrease phosphatidylinositol 3 kinase (PI3K) phosphorylation levels and attenuate phosphorylated AKT and glycogen synthase kinase-3 β (GSK3β), while ectopic PPA1 expression had the opposite effects. Moreover, PI3K inhibitors suppress the signaling pathways mediating the effects of PPA1 on breast cancer, resulting in tumor growth and metastasis suppression in vitro and in vivo. In summary, our results verify that PPA1 can act as an activator of PI3K/AKT/GSK3β/Slug-mediated breast cancer progression and that it is a potential therapeutic target for the inhibition of tumor progression.
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Project description:Colorectal cancer is the most common gastrointestinal cancer and causes severe damage to human health. PRDX2 is a member of the peroxiredoxin family reported to have a high level of expression in colorectal cancer. However, the mechanisms by which PRDX2 promotes the proliferation of colorectal cancer are still unclear. Here, the results indicated that PRDX2 expression was upregulated in colorectal cancer and closely correlated with poor prognosis. Functionally, PRDX2 promoted the proliferation of colorectal cancer cells. Mechanistically, PRDX2 could bind RPL4, reducing the interaction between RPL4 and MDM2. These findings demonstrate that the oncogenic property of PRDX2 may be attributed to its regulation of the RPL4-MDM2-p53 pathway, leading to p53 ubiquitinated degradation.
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Project description:BackgroundProstate cancer (PCa) is one of the most common cancers in male worldwide. Oxidative stress has been recognized as one of the driving signals pathologically linked to PCa progression. Nevertheless, the association of oxidative stress with PCa progression remains unclear.MethodsWestern blot, q-RT-PCR and bioinformatics analyses were used to examine PAGE4 expression. Comet assay and Annexin V/ PI dual staining assay were performed to investigate DNA damage and cell death under oxidative stress. Mouse xenograft model of PCa cells was established to verify the role of PAGE4 in vivo. Transcriptomic analysis was performed to investigate the underlying mechanism for the function of PAGE4 under oxidative stress. Western blot assay was conducted to determine the status of MAPK pathway. Immunohistochemistry was used to identify protein expression of PAGE4 in tumor tissues.ResultsIn this study, we found that PAGE4 expression was increased in PCa cells under oxidative stress condition. PAGE4 overexpression protected PCa cells from oxidative stress-inducing cell death by reducing DNA damage. PAGE4 overexpression promoted PCa cells growth in vivo. Mechanistically, PAGE4 promoted the survival of prostate cancer cells through regulating MAPK pathway which reflected in decreasing the phosphorylation of MAP2K4, JNK and c-JUN but increasing phosphorylation of ERK1/2.ConclusionOur findings indicate that PAGE4 protects PCa cells from DNA damage and apoptosis under oxidative stress by modulating MAPK signalling pathway. PAGE4 expression may serve as a prognostic biomarker for clinical applications.
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Project description:PRDM family proteins are dysregulated in many human diseases, especially hematological malignancies and solid cancers, and share a unique N-terminal PR domain followed by zinc fingers toward the C terminus. With a high frequency of DNA promoter hypermethylation, PRDM5 is primarily considered as a tumor suppressor in solid tumors. However, little is known about the function of PRDM5 in blood malignancies, especially acute myeloid leukemia (AML). In this study, we showed that high PRDM5 expression levels were independently correlated with poor overall survival in AML patients. PRDM5 overexpression promoted cell proliferation, colony formation, and migration in vitro and enhanced tumorigenesis in an in vivo xenograft model. Furthermore, we found that PRDM5 overexpression promoted cell cycle progression with the decreased level of cell cycle inhibitors such as p16 and p21, and regulated the expression of epithelial-mesenchymal transition markers ZO-1 and Vimentin to promote migration. Moreover, we observed that PRDM5 upregulated the Jun N-terminal kinase (JNK) signaling pathway and downregulated c-Myc expression. Pharmacological inhibition of JNK by SP600125 partially abrogated PRDM5-induced cell proliferation and migration. Taken together, our findings demonstrate that PRDM5 functions as an oncogenic driver in AML via JNK pathway, suggesting that PRDM5 is a potential therapeutic target for AML.
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Project description:Hes1 is a transcription factor that influences cell proliferation and differentiation. However, the effect of Hes1 on invasiveness and the underlying mechanism remain unknown. In the current study, we found that Hes1 suppressed cell apoptosis, promoted cell growth, induced EMT phenotype and cytoskeleton reconstruction, and enhanced the metastatic potential of colon cancer cells in vitro and in vivo. Furthermore, we indicated that Bmi-1 mediated Hes1-induced cell proliferation and migration, downregulated PTEN and activated the Akt/GSK3β pathway, consequently induced EMT and cytoskeleton reconstruction, ultimately leading to enhanced invasiveness of cancer cells. In addition, we also found that both Hes1 and Bmi-1 could directly regulate PTEN by associating at the PTEN locus, and played important roles in regulating PTEN/Akt/GSK3β pathway. Our results provide functional and mechanistic links between Hes1 and Bmi-1/PTEN/Akt/GSK3β signaling in the development and progression of colon cancer.
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Project description:BackgroundGanoderma sp., such as Ganoderma tsugae (GT), play an important role in traditional Chinese medicine. Ganoderma sp. contains several constituents, including Sacacchin, which has recently drawn attention because it can not only enhance the repair of muscle damage but also strengthen the muscle enforcement. Although Ganoderma sp. have a therapeutic effect for neuromuscular disorders, the underlying mechanism remains unclear. This study investigated the effect and underlying molecular mechanism of micronized sacchachitin (mSC) on satellite cells (SCs), which are known as the muscle stem cells.MethodsThe myogenic cells, included SCs (Pax7+) were isolated from tibialis anterior muscles of a healthy rat and were cultured in growth media with different mSC concentrations. For the evaluation of SC proliferation, these cultivated cells were immunostained with Pax7 and bromodeoxyuridine assessed simultaneously. The molecular signal pathway was further investigated by using Western blotting and signal pathway inhibitors.ResultsOur data revealed that 200 µg/mL mSC had an optimal capability to significantly enhance the SC proliferation. Furthermore, this enhancement of SC proliferation was verified to be involved with activation of TAK1-JNK-AP-1 signaling pathway through TLR2, whose expression on SC surface was confirmed for the first time here.ConclusionMicronized sacchachitin extracted from GT was capable of promoting the proliferation of SC under a correct concentration.
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Project description:The E3 ubiquitin ligase adaptor Speckle-type POZ protein (SPOP) plays an important tumour suppressor role in prostate cancers (PCa), with mutation rate up to 15%. However, how SPOP mutations regulate prostate tumorigenesis remains elusive. Here, we report the identification of cell division cycle associated 5 (CDCA5) as a SPOP substrate. We found that SPOP interacts with CDCA5 and promotes its polyubiquitin degradation in a degron-dependent manner. This effect was greatly impaired by introducing PCa associated SPOP mutations. Importantly, we found that CDCA5 was essential for PCa cells to survive and proliferate. CDCA5 depletion in PCa cells led to cessation of proliferation, G2M arrest, severe sister chromatid aggregation disturbance, and apoptosis. we also found that CDCA5 knockdown decreased the protein expression of p-GSK3β, increased the activity of caspase-3, caspase-9, and the Bax/Bcl-2 ratio. Besides, we confirmed that CDCA5 interrupted cancer cell behavior via the AKT pathway. In contrast, silencing SPOP or overexpressing CDCA5 increased cell proliferation. Consistently, depleting SPOP along with CDCA5, or overexpressing CDCA5 along with SPOP also caused the growth of cells repressed. Consistent with the functional role of CDCA5, the mRNA and protein levels of CDCA5 were significantly increased in PCa, compared to normal tissues, and its high expression was associated with more severe lymph node metastasis, higher Gleason score, and poorer prognosis. Together, our data showed that SPOP plays a crucial role in inhibiting tumorigenesis and partly achieved this by promoting the degradation of oncoprotein CDCA5.
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