Homo sapiens
Ontology highlight
ABSTRACT:
OTHER RELATED OMICS DATASETS IN: E-GEOD-33950
PROVIDER: PRJNA150029 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:SHARP1 suppresses breast cancer metastasis by promoting degradation of hypoxia-inducible factors
2025-01-24 | E-GEOD-33950 | ExpressionAtlas
Project description:Metastasis is responsible for the majority of breast cancer (BrCa) deaths; however, the underlying mechanisms remain largely elusive. Here, we report that suppression of MBD2 alternative splicing under hypoxia, which favors the production of MBD2a, facilitates BrCa metastasis. Specifically, we found that MBD2a promotes, whereas its less-known short form MBD2c suppresses metastasis. We elucidate that HIF-1 activation under hypoxia facilitates MBD2a production via repression of SRSF2-mediated alternative splicing and, as a result, the elevated MBD2a outcompetes MBD2c for binding to the promoter CpG islands to activate the expression of FZD1, thereby promoting EMT and metastasis. Strikingly, clinical data reveals significantly correlated expression pattern of MBD2a and MBD2c with the invasiveness of malignancy, indicating the opposing roles for MBD2 splicing variants in regulating human BrCa metastasis. Thus, our findings establish a novel link between MBD2 switching and tumor metastasis, and provide promising therapeutic strategy and predictive biomarkers for hypoxia-driven BrCa metastasis.
2021-02-01 | GSE151952 | GEO
Project description:Hypoxia is a common feature of many solid tumors due to aberrant proliferation and angiogenesis that is associated with tumor progression and metastasis. Most of the well-known hypoxia effects are mediated through hypoxia-inducible factors (HIFs). Identification of the long-lasting effects of hypoxia beyond the immediate HIF-induced alterations could provide a better understanding of hypoxia-driven metastasis and potential strategies to circumvent it. Here, we uncovered a hypoxia-induced mechanism that exerts a prolonged effect to promote metastasis. In breast cancer patient-derived circulating tumor cell (CTC) lines and common breast cancer cell lines, hypoxia downregulated tumor intrinsic type I interferon (IFN) signaling and its downstream antigen presentation (AP) machinery in luminal breast cancer cells, via both HIF-dependent and HIF-independent mechanisms. Hypoxia induced durable IFN/AP suppression in certain cell types that was sustained after returning to normoxic conditions, presenting a “hypoxic memory” phenotype. Hypoxic memory of IFN/AP downregulation was established by specific hypoxic priming, and cells with hypoxic memory had an enhanced ability for tumorigenesis and metastasis. Overexpression of IRF3 enhanced IFN signaling and reduced tumor growth in normoxic, but not hypoxic, conditions. The histone deacetylase inhibitor (HDACi) entinostat upregulated IFN targets and erased the hypoxic memory. These results point to a mechanism by which hypoxia facilitates tumor progression through a long-lasting memory that provides advantages for CTCs during the metastatic cascade.
2024-06-28 | GSE269984 | GEO
Project description:Hypoxia is a common feature of many solid tumors due to aberrant proliferation and angiogenesis that is associated with tumor progression and metastasis. Most of the well-known hypoxia effects are mediated through hypoxia-inducible factors (HIFs). Identification of the long-lasting effects of hypoxia beyond the immediate HIF-induced alterations could provide a better understanding of hypoxia-driven metastasis and potential strategies to circumvent it. Here, we uncovered a hypoxia-induced mechanism that exerts a prolonged effect to promote metastasis. In breast cancer patient-derived circulating tumor cell (CTC) lines and common breast cancer cell lines, hypoxia downregulated tumor intrinsic type I interferon (IFN) signaling and its downstream antigen presentation (AP) machinery in luminal breast cancer cells, via both HIF-dependent and HIF-independent mechanisms. Hypoxia induced durable IFN/AP suppression in certain cell types that was sustained after returning to normoxic conditions, presenting a “hypoxic memory” phenotype. Hypoxic memory of IFN/AP downregulation was established by specific hypoxic priming, and cells with hypoxic memory had an enhanced ability for tumorigenesis and metastasis. Overexpression of IRF3 enhanced IFN signaling and reduced tumor growth in normoxic, but not hypoxic, conditions. The histone deacetylase inhibitor (HDACi) entinostat upregulated IFN targets and erased the hypoxic memory. These results point to a mechanism by which hypoxia facilitates tumor progression through a long-lasting memory that provides advantages for CTCs during the metastatic cascade.
2024-06-28 | GSE270295 | GEO
Project description:Hypoxia and dysregulation of three-dimensional (3D) chromatin architecture can both activate oncogenic transcriptomic profiles, thus contributing to tumor malignancy. But how hypoxia regulates 3D chromatin architecture remains unknown. Here, we find that the transcription factor, zinc fingers and homeoboxes 2 (ZHX2), generates liquid-liquid phase separation (LLPS) under hypoxia, thus promoting its occupancy on chromatin and activating transcription for a cluster of oncogenes, that is enriched by metastatic genes distinct from targets of hypoxia-inducible factor (HIF) and pathologically relevant to breast cancer. Mechanistically, hypoxia induces the LLPS of ZHX2 via a proline-rich intrinsically disordered region (IDR) in the nuclear localization sequence (NLS), thereby enhancing the phosphorylation of ZHX2 at S625 and S628 that incorporates CCCTCbinding factor (CTCF) in condensates to reorganize chromatin looping, consequently resulting in oncogenic super-enhancer formation and breast cancer metastasis. This fundamental mechanism provides significant insight into oncogene activation and suggests a phase separation-based therapeutic strategy for cancer.
2025-03-18 | GSE260880 | GEO
Project description:Hypoxia and dysregulation of three-dimensional (3D) chromatin architecture can both activate oncogenic transcriptomic profiles, thus contributing to tumor malignancy. But how hypoxia regulates 3D chromatin architecture remains unknown. Here, we find that the transcription factor, zinc fingers and homeoboxes 2 (ZHX2), generates liquid-liquid phase separation (LLPS) under hypoxia, thus promoting its occupancy on chromatin and activating transcription for a cluster of oncogenes, that is enriched by metastatic genes distinct from targets of hypoxia-inducible factor (HIF) and pathologically relevant to breast cancer. Mechanistically, hypoxia induces the LLPS of ZHX2 via a proline-rich intrinsically disordered region (IDR) in the nuclear localization sequence (NLS), thereby enhancing the phosphorylation of ZHX2 at S625 and S628 that incorporates CCCTCbinding factor (CTCF) in condensates to reorganize chromatin looping, consequently resulting in oncogenic super-enhancer formation and breast cancer metastasis. This fundamental mechanism provides significant insight into oncogene activation and suggests a phase separation-based therapeutic strategy for cancer.
2025-03-18 | GSE260794 | GEO
Project description:Hypoxia and dysregulation of three-dimensional (3D) chromatin architecture can both activate oncogenic transcriptomic profiles, thus contributing to tumor malignancy. But how hypoxia regulates 3D chromatin architecture remains unknown. Here, we find that the transcription factor, zinc fingers and homeoboxes 2 (ZHX2), generates liquid-liquid phase separation (LLPS) under hypoxia, thus promoting its occupancy on chromatin and activating transcription for a cluster of oncogenes, that is enriched by metastatic genes distinct from targets of hypoxia-inducible factor (HIF) and pathologically relevant to breast cancer. Mechanistically, hypoxia induces the LLPS of ZHX2 via a proline-rich intrinsically disordered region (IDR) in the nuclear localization sequence (NLS), thereby enhancing the phosphorylation of ZHX2 at S625 and S628 that incorporates CCCTCbinding factor (CTCF) in condensates to reorganize chromatin looping, consequently resulting in oncogenic super-enhancer formation and breast cancer metastasis. This fundamental mechanism provides significant insight into oncogene activation and suggests a phase separation-based therapeutic strategy for cancer.
2025-03-18 | GSE260792 | GEO
Project description:Hypoxia and dysregulation of three-dimensional (3D) chromatin architecture can both activate oncogenic transcriptomic profiles, thus contributing to tumor malignancy. But how hypoxia regulates 3D chromatin architecture remains unknown. Here, we find that the transcription factor, zinc fingers and homeoboxes 2 (ZHX2), generates liquid-liquid phase separation (LLPS) under hypoxia, thus promoting its occupancy on chromatin and activating transcription for a cluster of oncogenes, that is enriched by metastatic genes distinct from targets of hypoxia-inducible factor (HIF) and pathologically relevant to breast cancer. Mechanistically, hypoxia induces the LLPS of ZHX2 via a proline-rich intrinsically disordered region (IDR) in the nuclear localization sequence (NLS), thereby enhancing the phosphorylation of ZHX2 at S625 and S628 that incorporates CCCTCbinding factor (CTCF) in condensates to reorganize chromatin looping, consequently resulting in oncogenic super-enhancer formation and breast cancer metastasis. This fundamental mechanism provides significant insight into oncogene activation and suggests a phase separation-based therapeutic strategy for cancer.
2025-03-18 | GSE260793 | GEO
Project description:Metastatic colorectal cancer (mCRC) is the major cause of death in patients with CRC. Hypoxia is a hallmark of solid tumors that promotes cell metabolic adaptation and metastasis. However, the mechanism linking mCRC to hypoxia-regulated metabolic adaptation remains unclear. Here, we found that inorganic pyrophosphatase 2 (PPA2) suppresses mCRC progression via its phosphatase function. PPA2 is expressed at low levels in mCRC specimens and lowly expressed PPA2 mediates better responses to hypoxia to enhance CRC glycolysis and metastasis by promoting hypoxia-inducible factor-1α (HIF-1α) signaling. Mechanistically, PPA2 decreases HIF-1α stability through noncanonical ubiquitin-mediated proteasomal degradation via recruitment of E3 ligase neural precursor cell-expressed developmentally downregulated gene 4 (NEDD4), which inhibits glycolysis and metastasis-related gene expression. Furthermore, PPA2 directly interacts with NEDD4 and dephosphorylates NEDD4 at the T758 residue, leading to the increased interaction between NEDD4 and HIF-1α. Under hypoxic stress, NAD-dependent protein deacetylase sirtuin-5 (SIRT5) promotes the dissociation of PPA2 and NEDD4 by inducing PPA2 desuccinylation at the K176 residue, which ultimately contributes to the improved stability of HIF-1α under hypoxic conditions. Our findings reveal the suppressive role of PPA2 in HIF-1α-dependent mCRC, suggesting that the SIRT5-PPA2-NEDD4-HIF-1α axis can be assessed for integrated prognosis evaluation and represents a potential therapeutic target.
2024-12-01 | GSE276272 | GEO