Fas-associated factor 1 (FAF1) is a multidomain protein that interacts with diverse partners to affect numerous cellular processes. Previously, we discovered two Small Ubiquitin-like Modifier ...(SUMO)-interacting motifs (SIMs) within FAF1 that are crucial for transcriptional modulation of mineralocorticoid receptor. Recently, we identified Sin3A-associated protein 130 (SAP130), a putative sumoylated protein, as a candidate FAF1 interaction partner by yeast two-hybrid screening. However, it remained unclear whether SAP130 sumoylation might occur and functionally interact with FAF1.
In this study, we first show that SAP130 can be modified by SUMO1 at Lys residues 794, 878 and 932 both in vitro and in vivo. Mutation of these three SUMO-accepting Lys residues to Ala had no impact on SAP130 association with Sin3A or its nuclear localization, but the mutations abrogated the association of SAP130 with the FAF1. The mutations also potentiated SAP130 trans-repression activity and attenuated SAP130-mediated promotion of cell growth. Additionally, SUMO1-modified SAP130 was less stable than unmodified SAP130. Transient transfection experiments further revealed that FAF1 mitigated the trans-repression and cell proliferation-promoting functions of SAP130, and promoted SAP130 degradation by enhancing its polyubiquitination in a sumoylation-dependent manner.
Together, these results demonstrate that sumoylation of SAP130 regulates its biological functions and that FAF1 plays a crucial role in controlling the SUMO-dependent regulation of transcriptional activity and protein stability of SAP130.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
During brain development, the expression of promyelocytic leukemia zinc finger (Plzf) in neural stem cells is precisely controlled to maintain the balance between neural stem cell self-renewal and ...differentiation. However, the mechanism underlying transcriptional regulation of Plzf in neural stem cell is still unclear. Herein, using P19 embryonal carcinoma cells as a model, we observed that Plzf expression was induced in the P19-derived embryonic bodies, which enrich neural stem-like cell populations, as demonstrated by the expression of neural stem cell markers, Nestin and Sox2. We then characterized the Plzf promoter and identified two E2f1 binding sites (−755/-751 and −53/-49, the transcription start site was designated as +1) are important for the activation of Plzf promoter. Finally, we found that the induction of Plzf in the neural stem-like cells derived from pluripotent P19 cells is decrease by E2f1 knockdown. Taken together, we conclude that E2f1 is an important transcription factor that regulates Plzf transcription and may involve in maintaining the self-renewal ability of neural stem cells.
•Plzf expression is induced in the neural stem-like cells derived from pluripotent P19 embryonal carcinoma cells.•E2f1 up-regulates Plzf promoter activity in P19 cells.•Two E2f1 binding sites (−755/-751 and −53/-49) are sufficient for the activation of Plzf promoter.•The induction of Plzf in the neural stem-like cells derived from pluripotent P19 cells is decreased by E2f1 knockdown.
Colorectal cancer (CRC) is one of the world's leading causes of cancer-related deaths; thus, it is important to detect it as early as possible. Obesity is thought to be linked to a large rise in the ...CRC incidence as a result of bad dietary choices, such as a high intake of animal fats. Fatty acid-binding proteins (FABPs) are a set of molecules that coordinate intracellular lipid responses and are highly associated with metabolism and inflammatory pathways. There are nine types of
genes that have been found in mammals, which are
,
, and
. Each
gene has its own roles in different organs of the body; hence, each one has different expression levels in different cancers. The roles of
family genes in the development of CRC are still poorly understood. We used a bioinformatics approach to examine
family gene expression profiles using the Oncomine, GEPIA, PrognoScan, STRING, cBioPortal, MetaCore, and TIMER platforms. Results showed that the
messenger (m)RNA level is overexpressed in CRC cells compared to normal cells. The overexpression of
was found to be related to poor prognosis in CRC patients' overall survival. The immunohistochemical results in the Human Protein Atlas showed that FABP1 and FABP6 exhibited strong staining in CRC tissues. An enrichment analysis showed that high expression of
was significantly correlated with the role of microRNAs in cell proliferation in the development of CRC through the insulin-like growth factor (IGF) signaling pathway.
functions as an intracellular bile-acid transporter in the ileal epithelium. We looked at
expression in CRC since bile acids are important in the carcinogenesis of CRC. In conclusion, high
expression is expected to be a potential biomarker for detecting CRC at the early stage.
Pancreatic ductal adenocarcinoma (PDAC) is a highly fatal malignancy with poor survival outcomes. In addition, oxysterol-binding protein-like (OSBPL) family members are reported to be involved in ...lipid binding and transport and play critical roles in tumorigenesis. However, relationships between PDAC and OSBPL family members have not comprehensively been elucidated. In this study, we used the Oncomine and GEPIA 2 databases to analyze OSBPL transcription expressions in PDAC. The Kaplan–Meier plotter and TIMER 2.0 were used to assess the relationships between overall survival (OS) and immune-infiltration with OSBPL family members. Co-expression data from cBioPortal were downloaded to assess the correlated pathways with OSBPL gene family members using DAVID. The expressions of OSBPL3, OSBPL8, OSBPL10, and OSBPL11 were found to be highly upregulated in PDAC. Low expressions of OSBPL3, OSBPL8, and OSBPL10 indicated longer OS. The functions of OSBPL family members were mainly associated with several potential signaling pathways in cancer cells, including ATP binding, integrin binding, receptor binding, and the renin-angiotensin system (RAS) signaling pathway. The transcription levels of OSBPL gene family members were connected with several immune infiltrates. Collectively, OSBPL family members are influential biomarkers for the early diagnosis of PDAC and have prognostic value, with the promise of precise treatment of PDAC in the future.
Early-onset colorectal cancer (EoCRC) constitutes 2%–10% of all colorectal cancers and is becoming more common globally. Diabetes mellitus (DM) has increased substantially in younger adults; however, ...its involvement in EoCRC remains unclear. We conducted a systematic review and meta-analysis of observational studies to (1) explore the prevalence of DM in individuals with EoCRC and (2) investigate the association between DM and EoCRC.
A systematic literature search was conducted to identify studies published before May 2022 that evaluated the association between DM and EoCRC risk in four databases, including Medline (PubMed), Embase, Web of Science, and the Cochrane Central Register of Controlled Trials. Results from the studies were summarized in meta-analyses using random effects models.
Nineteen eligible studies were included. A total of 33,359 EoCRC cases and 14,259,289 controls in 12 studies were included in the meta-analysis. The pooled odds ratio OR of 1.43 (95% confidence interval CI: 1.08–1.8) indicated significant positive association between DM and increased risk of EoCRC. Subgroup analysis demonstrated that diabetes severity was significantly associated with unmanaged DM (OR = 1.28, 95% CI: 1.02–1.6), but not with managed DM (OR = 1.04, 95% CI: 0.84–1.28).
Our results suggest that DM is a risk factor for EoCRC, and the higher prevalence of DM among younger adults may contribute to the increasing incidence of EoCRC. Interventions to reduce this bidirectional risk should be further investigated for the development of effective prevention and treatment strategies. PROSPERO registration: CRD42022306347.
•This study collected large sample size using a multicenter, multinational, multiracial, and multicontinental approach.•The rising prevalence of DM among younger adults may partially contribute to the increasing incidence of EoCRC.•Active screening for diabetes should be considered in EoCRC patients.
The development and progression of colorectal cancer (CRC) involve changes in genetic and epigenetic levels of oncogenes and/or tumor suppressors. In spite of advances in understanding of the ...molecular mechanisms involved in CRC, the overall survival rate of CRC still remains relatively low. Thus, more research is needed to discover and investigate effective biomarkers and targets for diagnosing and treating CRC. The roles of long non-coding RNAs (lncRNAs) participating in various aspects of cell biology have been investigated and potentially contribute to tumor development. Our recent study also showed that CRNDE was among the top 20 upregulated genes in CRC clinical tissues compared to normal colorectal tissues by analyzing a Gene Expression Omnibus (GEO) dataset (GSE21815). Although CRNDE is widely reported to be associated with different types of cancer, most studies of CRNDE were limited to examining regulation of its transcription levels, and in-depth mechanistic research is lacking. In the present study, CRNDE was found to be significantly upregulated in CRC patients at an advanced TNM stage, and its high expression was correlated with poor outcomes of CRC patients. In addition, we found that knocking down CRNDE could reduce lipid accumulation through the miR-29b-3p/ANGPTL4 axis and consequently induce autophagy of CRC cells.
Stereotactic ablative radiotherapy (SABR) may improve survival in patients with inoperable pulmonary oligometastases. However, the impact of pulmonary oligometastatic status after systemic therapy on ...SABR outcomes remains unclear. Hence, we investigated the outcomes of SABR in 45 patients with 77 lung tumors and the prognostic value of pulmonary oligoprogression. Eligibility criteria were pulmonary oligometastases (defined as ≤5 metastatic lung tumors), controlled extrapulmonary disease (EPD) after front-line systemic therapy, SABR as primary local treatment for inoperable pulmonary metastases, and consecutive imaging follow-up. Oligometastatic lung tumor was classified into controlled or oligoprogressive status. Overall survival (OS), in-field progression-free survival (IFPFS), out-field progression-free survival (OFPFS), and prognostic variables were evaluated. With 21.8 months median follow-up, the median OS, IFPFS, and OFPFS were 28.3, not reached, and 6.5 months, respectively. Two-year OS, IFPFS, and OFPFS rates were 56.0%, 74.2%, and 17.3%, respectively. Oligoprogressive status (
= 0.003), disease-free interval < 24 months (
= 0.041), and biologically effective dose (BED
) < 100 Gy (
= 0.006) were independently associated with inferior OS. BED
≥ 100 Gy (
= 0.029) was independently correlated with longer IFPFS. Oligoprogressive status (
= 0.017) and EPD (
= 0.019) were significantly associated with inferior OFPFS. Grade ≥ 2 radiation pneumonitis occurred in four (8.9%) patients. Conclusively, SABR with BED
≥ 100 Gy could provide substantial in-field tumor control and longer OS for systemic therapy respondents with inoperable pulmonary oligometastases. Oligoprogressive lung tumors exhibited a higher risk of out-field treatment failure and shorter OS. Hence, systemic therapy should be tailored for patients with oligoprogression to reduce the risk of out-field treatment failure. However, in the absence of effective systemic therapy, SABR is a reasonable alternative to reduce resistant tumor burden.
Pin1 was the first prolyl isomerase identified that is involved in cell division. The mechanism by which Pin1 acts as a negative regulator of mitotic activity in G2 phase remains unclear. Here, we ...found that Aurora A can interact with and phosphorylate Pin1 at Ser16, which suppresses the G2/M function of Pin1 by disrupting its binding ability and mitotic entry. Our results also show that phosphorylation of Bora at Ser274 and Ser278 is crucial for binding of Pin1. Through the interaction, Pin1 can alter the cytoplasmic translocation of Bora and promote premature degradation by β-TrCP, which results in a delay in mitotic entry. Together with the results that Pin1 protein levels do not significantly fluctuate during cell-cycle progression and Aurora A suppresses Pin1 G2/M function, our data demonstrate that a gain of Pin1 function can override the Aurora-A-mediated functional suppression of Pin1. Collectively, these results highlight the physiological significance of Aurora-A-mediated Pin1 Ser16 phosphorylation for mitotic entry and the suppression of Pin1 is functionally linked to the regulation of mitotic entry through the Aurora-A-Bora complex.
Malignant glioblastoma multiforme (GBM) is an aggressive brain tumor with strong local invasive growth and a poor prognosis. One probable way to manipulate GBM cells toward a less invasive status is ...to reprogram the most malignant GBM cells to a more differentiated and less oncogenic phenotype. Herein, we identified a novel role of a RING finger protein Znf179 in gliomagenesis. Znf179 overexpression induced differentiation of primary GBM cells, which were accompanied with elevated glial fibrillary acidic protein (GFAP) expression through up-regulating several cell-cycle-related factors, p53, p21, and p27, and allowed the cell-cycle arrest in the G
/G
phase. In addition, Znf179 was highly correlated with the prognosis and survival rates of glioma patients. The expression levels of Znf179 was relatively lower in glioma patients compared to normal people, and glioma patients with lower expression levels of Znf179 mRNA had poorer prognosis and lower survival rates. In conclusion, we provide novel insight that Znf179 can reprogram GBM cells into a more-differentiated phenotype and prevent the progression of gliomas to a more-malignant state through p53-mediated cell-cycle signaling pathways. Understanding the molecular mechanism of Znf179 in gliomagenesis could help predict prognostic consequences, and targeting Znf179 could be a potential biomarker for glioma progression.
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