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Transcriptional elongation control of hypoxic response and therapeutic approaches

ABSTRACT: Transcriptional elongation control of hypoxic response and therapeutic approaches

PROVIDER: PRJNA1024499 | ENA |

REPOSITORIES: ENA

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Transcriptional elongation control of hypoxic response and therapeutic approaches

Project description:The release of paused RNA polymerase II (RNAPII) from promoter-proximal regions is tightly controlled to ensure proper regulation of gene expression. The elongation factor PTEF-b is known to release paused RNAPII via phosphorylation of the RNAPII C-terminal domain by its cyclin-dependent kinase component, CDK9. However, the signal and stress-specific roles of the various RNAPII-associated macromolecular complexes containing PTEF-b/CDK9 are not yet clear. Here, we identify and characterize the CDK9 complex required for transcriptional response to hypoxia. Contrary to previous reports, our data indicate that a CDK9 complex containing BRD4 but not AFF1/4 is essential for this hypoxic stress response. We demonstrate that BRD4 bromodomains (BET) are dispensable for the release of paused RNAPII at hypoxia-activated genes and that BET inhibition by JQ1 is insufficient to impair hypoxic gene response. Mechanistically, we demonstrate that the C-terminal region of BRD4 is required for Polymerase-Associated Factor-1 Complex (PAF1C) recruitment to establish an elongation-competent RNAPII complex at hypoxia-responsive genes. PAF1C disruption using a small-molecule inhibitor (iPAF1C) impairs hypoxia-induced, BRD4-mediated RNAPII release. Together, our results provide insight into potentially targetable mechanisms that control the hypoxia-responsive transcriptional elongation.

2024-06-27 | GSE244754 | GEO

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Temporal proteomic analysis unravels the hypoxic response of melanoma cells

Project description:Hypoxia is a common feature in various solid tumors including melanoma. Cancer cells in hypoxic environments are resistant to both chemotherapy and radiation. Hypoxia is also associated with immune suppression. Identification of proteins and pathways that regulate survival of cancer cells in hypoxic environments can reveal potential vulnerabilities that can be exploited to improve efficacy of anti-cancer therapy. We carried out global proteome and phosphoproteome profiling in melanoma cell lines to identify proteins and pathways that are induced by hypoxia. Here, using Orbitrap Fusion Mass Spectrometer for analysis and employing TMT-based quantitation, we report >7,000 proteins and >10,000 phosphosites. As expected, several proteins that are known targets of hypoxia inducible factors (HIFs) were found to be overexpressed in the hypoxic models. In addition, several metabolic enzymes showed altered expression revealing metabolic reprogramming in hypoxic conditions. Phosphoproteomic profiling revealed kinase mediated signaling pathways that are induced in hypoxic conditions. Our data provides a comprehensive view of proteomic and phosphoproteomic alterations in hypoxia and reveals potential mechanisms that regulate cell survival in hypoxic environments. These mechanisms can be targeted to improve therapeutic outcomes in cancer treatment. Further, we identify the 20S proteasome as a putative therapeutic target in melanoma.

2021-05-31 | PXD019832 | Pride

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Project description:Experiments were performed assessing whether targeting the pH regulatory proteins (CAIX, NHE1 and V-ATPase) that permit cancer cells to adapt to hypoxic conditions could produce an effective therapeutic response in breast cancer, using both 2D and 3D culture models. CAIX inhibitors were shown to combine effectively with irradiation in clonogenic assays. Proteomic-mass-spectrometric analysis was carried out to analyze the possible mechanisms through which the CAIX inhibitor used was combining with irradiation.

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