Effect of HDAC2 siRNA on HCC
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE52232 | GEO | 2014/10/02
SECONDARY ACCESSION(S): PRJNA227202
REPOSITORIES: GEO
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Project description:Determine the effect and specificity of HDAC2 siRNA compared to SAHA inhibition of HDAC2 in hepatocellular carcinoma (HCC) Profile of treated cells compared to control Transcriptomic profiling
2014-10-02 | E-GEOD-52232 | biostudies-arrayexpress
Project description:Hepatocellular carcinoma (HCC) poses a severe threat to human health. The NET-1 protein has been proved to be strongly associated with HCC proliferation and metastasis in our previous study. Here, we established and validated NET-1 siRNA nanoparticles system to conduct targeted gene therapy of HCC xenograft in vivo with the aid of sonodynamic therapy (SDT). Then, a label-free proteome mass spectrometry workflow to analyze formalin-fixed and paraffin-embedded HCC xenograft samples collected in this study. The result showed that 78 proteins were differentially expressed after NET-1 protein inhibited. Among them, the expression of 61 proteins up-regulated and the expression of 17 proteins were significantly down-regulated. Of the differentially expressed proteins, the vast majority of Gene Ontology enrichment terms belong to the biological process. The KEGG pathway enrichment analysis showed that the 78 differentially expressed proteins significantly enriched in 45 pathways. We concluded that the function of the NET-1 gene is not only to regulate HCC but also to participate in a variety of biochemical metabolic pathways in the human body. Furthermore, the protein-protein interaction analysis indicated that the interactions of differentially expressed proteins are incredibly sophisticated. All the protein-protein interactions happened after the NET-1 gene has been silenced. Finally, our study also provides a useful proposal for targeted therapy based on tetraspanin proteins to treat HCC, and further mechanism investigations are needed to reveal a more detailed mechanism of action for NET-1 protein regulation of HCC.
2021-09-09 | PXD020763 | Pride
Project description:Objective: Advanced HCC patients have few choices for life-prolonging therapy due to the high incidence of drug resistance. This study aimed to clarify the mechanism of sorafenib resistance and seek more effective treatments.Design:Two sorafenib-resistant (SR) cell lines were established to study the mechanism of drug resistance. RNA sequencing was used to characterize the global transcriptional consequences of sorafenib resistance, and immunoprecipitation-mass spectrometry (IP-MS) was performed to identify specific acetylation sites.Results： We found that Rho-GTPases were upregulated in SR cells and that PLEKHG5 was most abundantly expressed among all Rho GEFs (activators of Rho-GTPases). PLEKHG5 knockdown increased HCC cell sensitivity to sorafenib and inhibited the activation of Rac1 and downstream AKT/NF-κB signaling, while overexpression of PLEKHG5 reduced sorafenib sensitivity, which suggested that PLEKHG5 activation could be targeted to limit sorafenib resistance. IP-MS confirmed that three lysine sites in PH domain of PLEKHG5 could be acetylated, and their acetylation levels were correlated with PLEKHG5 stability. Further study demonstrated that HDAC2 interacted with PLEKHG5 to deacetylate lysine sites within the PH domain and maintain its stability. Finally, both knockout of HDAC2 and treatment with the selective HDAC2 inhibitor CAY10683 reduced PLEKHG5 protein levels and thereby enhanced the sensitivity of HCC to sorafenib in vivo and in vitro.Conclusion.:PLEKHG5 plays a key role in the occurrence of sorafenib resistance by activating Rac1/AKT/NF-κB signaling. HDAC2 regulates PLEKHG5 protein stability by regulating the acetylation level of its PH domain, and thus HDAC2 may be a potential therapeutic target for overcoming PLEKHG5-mediated sorafenib resistance in HCC.
2021-06-05 | GSE176151 | GEO
Project description:This SuperSeries is composed of the following subset Series: GSE22366: Primary human erythroid progenitor cells HDAC1 and HDAC2 shRNA knockdown samples GSE22367: Primary human erythroid progenitor cells SAHA treatment samples GSE22368: Primary human erythroid progenitor cells NK57 treatment samples Refer to individual Series
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Project description:siRNA-mediated inhibition compared to untreated cells and cells transfected with nonsense siRNA. Loss of contact inhibition and anchorage-independent growth are hallmarks of cancer cells. In this context, frequent inactivation of the Hippo pathway and subsequent nuclear enrichment of the transcriptional coactivator yes-associated protein (YAP) uncouple cell proliferation and anti-apoptosis from contact inhibition, associated with uncontrolled tumor growth and tumor cell dissemination. However, general molecular mechanisms of tumor-supporting YAP activity remain unclear. In this study, we show that overexpression and nuclear accumulation of YAP in hepatocytes and hepatocellular carcinoma (HCC) cells leads to an induction of the Notch pathways through transcriptional activation of the Notch ligand jagged-1 (Jag-1). This induction of Jag-1 strictly depends on binding of YAP to TEAD4 and does not rely on WNT/β-catenin pathway activity. Co-activation of YAP, TEAD4, Jag-1, and the Notch target gene Hes-1 was significantly higher in HCC from patients with poor prognosis. High-level expression and nuclear accumulation of YAP correlates with Jag-1/Notch activation not only in human HCC tissues, but also in colon and pancreatic cancer tissues. Thus, our data demonstrate that YAP-driven co-activation of the Jag-1/Notch pathway in part facilitates oncogenic properties of the oncogene YAP not only in HCC but also in different gastrointestinal malignancies. Expression profiling of untreated HCC cell lines (control 1), cells transfected with scrambled/nonsense siRNA (control 2), and after siRNA-mediated YAP inhibition.
2012-11-01 | E-GEOD-35004 | biostudies-arrayexpress
Project description:ARID1A, encoding a subunit of the SWI/SNF chromatin remodeling complex, is the most frequently mutated epigenetic regulators in human cancers. ARID1A is mutated in over 50% ovarian clear cell carcinoma, a disease currently has no effective therapy. Here we show that ARID1A-mutated ovarian cancer cells are selectively sensitive to inhibition of HDAC2 activity. HDAC2 interacts with EZH2 in an ARID1A status dependent manner. HDAC2 knockdown inhibits the growth of ARID1A inactivated by not proficient ovarian cancer cells. HDAC2 functions as a co-repressor of EZH2 to suppress the expression of EZH2/ARID1A target tumor suppressor genes such as PIK3IP1, an inhibitor of PI3K/AKT signaling, to inhibit proliferation and promote apoptosis. Indeed, a FDA-approved pan-HDAC inhibitor suberoylannilide hydroxamine (SAHA) significantly suppressed the growth and reduced the ascites of the ARID1A-inactivated ovarian cancers in both orthotopic and genetic mouse models. This correlated with a significant improvement of survival of mice bearing ARID1A-mutated ovarian cancers.
2018-03-09 | GSE107201 | GEO
Project description:siRNA-mediated inhibition compared to untreated cells and cells transfected with nonsense siRNA Together with far upstream element binding protein (FBP), the FBP-interacting repressor (FIR) represents a molecular tool for the transcriptional fine tune regulation of target genes. Previous evidence indicates that strong overexpression of FBP in human hepatocellular carcinoma (HCC) supports tumor growth and correlates with poor patient prognosis. However, the role of the transcriptional repressor FIR in hepatocarcinogenesis remains poorly delineated. We show that overexpression of FIR correlates with tumor dedifferentiation and tumor cell proliferation in about 60% of primary HCCs. Elevated FIR levels are associated with genomic gains of the fir gene locus at chromosome 8q24.3 in human HCC specimens. In vitro, nuclear enrichment of FIR supports HCC cell proliferation and migration. Expression profiling of HCC cells after siRNA-mediated silencing of FIR identified the transcription factor DP-1 (TFDP1) as a transcriptional target of FIR. Surprisingly, FIR stimulates the expression of FBP in a TFDP1/E2F-dependent manner. FIR splice variants lacking or containing exon 2 and/or exon 5 are expressed in the majority of HCCs. Specific inhibition of FIR isoforms with and without exon 2 revealed that all FIR splice variants facilitate tumor-supporting effects. This finding was confirmed in xenograft transplantation experiments with lentiviral-infected shRNA targeting all FIR variants as well as FIR with and without exon 2. In summary, high-level nuclear FIR does not facilitate repressor properties but supports tumor growth in HCC cells. Thus, the pharmacological inhibition of FIR might represent a promising therapeutic strategy for HCC patients. Expression profiling of cells transfected with scrambled/nonsense siRNA (control), and after siRNA-mediated FIR inhibition.
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Project description:We analyzed the proteome of tumor and matched non-tumor biopsies from 51 treatment-naive Hepatocellular carcinoma (HCC) patients by DIA (SWATH). Thereby we aim to find subgroups of patients characterized by specific pathway activation. Furthermore, we aim to find novel factors involved in HCC development and novel biomarkers.
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