Targeting c-MYC by antagonizing PP2A inhibitors in breast cancer
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE58008 | GEO | 2014/05/28
SECONDARY ACCESSION(S): PRJNA248685
REPOSITORIES: GEO
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Project description:Inhibition of SET by siRNA or SET antagonist and CIP2A by siRNA can downregulate c-MYC and c-MYC target genes. Cells were treated with a SET antagonist (1μMOP449) for 12 hours, or siRNA for 48 hours.
2014-05-28 | E-GEOD-58008 | biostudies-arrayexpress
Project description:The transcription factor c-MYC is stabilized and activated by phosphorylation at serine 62 (S62) in breast cancer. Protein phosphatase 2A (PP2A) is a critical negative regulator of c-MYC through its ability to dephosphorylate S62. By inactivating c-MYC and other key signaling pathways, PP2A plays an important tumor suppressor function. Two endogenous inhibitors of PP2A, I2PP2A, Inhibitor-2 of PP2A (SET oncoprotein) and cancerous inhibitor of PP2A (CIP2A), inactivate PP2A and are overexpressed in several tumor types. Here we show that SET is overexpressed in about 50-60% and CIP2A in about 90% of breast cancers. Knockdown of SET or CIP2A reduces the tumorigenic potential of breast cancer cell lines both in vitro and in vivo. Treatment of breast cancer cells in vitro or in vivo with OP449, a novel SET antagonist, also decreases the tumorigenic potential of breast cancer cells and induces apoptosis. We show that this is, at least in part, due to decreased S62 phosphorylation of c-MYC and reduced c-MYC activity and target gene expression. Because of the ubiquitous expression and tumor suppressor activity of PP2A in cells, as well as the critical role of c-MYC in human cancer, we propose that activation of PP2A (here accomplished through antagonizing endogenous inhibitors) could be a novel antitumor strategy to posttranslationally target c-MYC in breast cancer.
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Project description:Inhibition of SET by siRNA or SET antagonist and CIP2A by siRNA can downregulate c-MYC and c-MYC target genes. Cells were treated with a SET antagonist (1μMOP449) for 12 hours, or siRNA for 48 hours.
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Project description:Abstract The protein phosphatase 2A (PP2A) heterotrimer PP2A-B56 is a human tumor suppressor. However, the molecular mechanisms inhibiting PP2A-B56in cancer are poorly understood. Here, we report molecular level details and structural mechanism of PP2A-B56inhibition by an oncoprotein CIP2A. Upon direct binding to PP2A-B56 trimer, CIP2A replaces PP2A-A subunit and thereby hijacks both the B56 and the catalytic PP2Ac subunit to form a CIP2A-B56-PP2Ac pseudotrimer. Further, CIP2A competes with B56 substrate binding by blocking the LxxIxE-motif substrate binding pocket on B56. Relevant to oncogenic activity of CIP2A across human cancers, the N-terminal head domain-mediated interaction with B56 stabilizes CIP2A protein. Functionally, CRISPR/Cas9-mediated single amino acid mutagenesis of the head domain blunted MYC expression and MEK phosphorylation, and abrogated triple-negative breast cancer in vivo tumor growth. Collectively, we discover a unique multi-step “hijack and mute” mechanism of protein complex regulation inhibiting tumor suppressor PP2A-B56. Further, the results unfold single structural determinant for CIP2A´s oncogenic activity, potentially facilitating therapeutic modulation of CIP2A in cancer and other diseases.
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Project description:The purpose is to study the transcriptional changes in basal like breast cancer cell line HCC38 on depletion of CIP2A. We have used 3 unique siRNA sequences of CIP2A and 3 control samples (Mock and 2 unique non-targeting sequences) for the RNA Seq. We identified differentially expressed genes in CIP2A knockdown conditions compared to the control samples and identified pathways regulated by CIP2A in this cell line using GSEA.
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Project description:Autophagy is important for removal, degradation and recycling of damaged organelles, proteins, and lipids through the degradative action of lysosomes. In addition to its catabolic function, autophagy is important in cancer and viral-mediated tumorigenesis, including Human Papillomavirus (HPV) positive cancers. HPV infection is a major risk factor in a subset of Head and Neck Cancer (HNC), for which no targeted therapies are currently available. Herein, we assessed autophagy function in HPV-positive HNC. We showed that HPV-positive HNC cells presented a transcriptional and functional impairment of autophagic process compared to HPV-negative cells, which was reactivated by knocking-down HPV E6/E7 oncoproteins, the drivers of cellular transformation. We found that the oncoprotein c-MYC was stabilized and triggered in HPV-positive cell lines. This resulted in the reduced binding of the MiT/TFE transcription factors to their autophagy targets due to c-MYC competition. Thus, knock-down of c-MYC induced the upregulation of autophagic and lysosomal genes in HPV-positive HNC cells, as well as the increase of autophagic markers at the protein level. Moreover, HPV oncoprotein E7 upregulated the expression of the phosphatase inhibitor CIP2A, accounting for c-MYC upregulation and stability in HPV+ HNC cells. CIP2A mRNA expression negatively correlated with autophagy gene expression in tumor tissues from HNC patients, showing, for the first time, its implication in a transcriptional autophagic context. Both CIP2A and c-MYC knock-down, as well as pharmacological downregulation of c-MYC, resulted in increased resistance to Cisplatin treatment. Our results not only show a novel way by which HPV oncoproteins manipulate the host machinery, but also provide more insights on the role of autophagy in chemoresistance, with possible implications for targeted HPV-positive HNC therapy.
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Project description:MYC-amplified medulloblastomas are highly lethal tumors. BET bromodomain inhibition was recently described to downregulate MYC-associated transcriptional activity in various cancer subtypes. To investigate whether JQ1, a BET bromodomain inhibitor is downregulation MYC and MYC-associated transcriptional activity, we performed global gene expression profiling of five medulloblastomas MYC-amplified patient-derived cell lines treated by JQ1 and the inactive form of JQ1. Five medulloblastomas patient-derived MYC-amplified cell lines were treated with the active and the inactive form of the drug (JQ1S or JQ1R, respectively, 1μM for 24 hours) followed by RNA extraction and hybridization on Affymetrix microarrays
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Project description:The generation of optimal immune response requires combined activation of both T- and B-cells. Here, we demonstrate that the cancerous inhibitor of protein phosphatase 2A (CIP2A) is a novel factor that governs activation of both T- and B-cells in vivo. Upon ovalbumin challenge, CIP2A-deficient (CIP2AHOZ) mice show impaired immune response. Furthermore, CIP2AHOZ mice had impaired clearance of Listeria Monocytogenesis (L.m.) infection, combined with decreased numbers of CD8+ T-cells and IFN-? secretion. In an ovalbumin model of allergic asthma, CIP2AHOZ B-cells were impaired in IgE and IgG secretion, despite of normal Th2 differentiation and unaffected numbers of inflammatory cells or cytokines in bronchoalveolar lavage. Importantly, the cell-autonomous effect of CIP2A deficiency for both T- and B-cell activation was confirmed by in vitro assays. During the T-cell activation CIP2A, was shown to promote expression of ETS-1, whereas in B-cells CIP2A loss resulted in inhibition of MYC-mediated gene expression. Together these results identify CIP2A as a novel cell-autonomous regulator governing both T- and B-cell activation in vivo. They also identify CIP2AHOZ as a novel murine model for investigation of impaired immune response and allergic asthma. Total RNA obtained from 4 male mutant mice was compared to 4 wild type controls.
2015-06-10 | E-GEOD-56401 | biostudies-arrayexpress