Liquid-liquid phase separation of ZHX2 protects DLBCL cells against ferroptosis through induction of SLC3A2
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PROVIDER: PRJNA1240601 | ENA |
REPOSITORIES: ENA
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Project description:Diffuse large B-cell lymphoma (DLBCL), the most common B-cell non-Hodgkin lymphoma (B-NHL), is characterized by strong aggression, high heterogeneity and poor prognosis. Consequently, there is an urgent need to identify crucial therapeutic targets. Here, we found that the transcription factor Zinc-finger and homeoboxes 2 (ZHX2) is highly expressed in DLBCL. Subsequently, ZHX2 was proven to be critical for promoting DLBCL cells proliferation by inhibiting ferroptosis. Mechanistically, ZHX2 binds to the promoter region of the solute carrier family 3-member 2 (SLC3A2) gene through liquid-liquid phase separation (LLPS) and activates its function to negatively regulate ferroptosis. Furthermore, we constructed lipid nanoparticles Zhx2-siRNA@LNP targeting DLBCL, which effectively inhibited the growth of the tumor in vivo. In summary, our study indicated that LLPS of ZHX2 protects DLBCL against ferroptosis through induction of SLC3A2, and disturbing it with Zhx2-siRNA@LNP could significantly repress DLBCL, providing a promising therapeutic strategy for DLBCL.
2025-07-30 | GSE292652 | GEO
Project description:Diffuse large B-cell lymphoma (DLBCL), the most common B-cell non-Hodgkin lymphoma (B-NHL), is characterized by strong aggression, high heterogeneity and poor prognosis. Consequently, there is an urgent need to identify crucial therapeutic targets. Here, we found that the transcription factor Zinc-finger and homeoboxes 2 (ZHX2) is highly expressed in DLBCL. Subsequently, ZHX2 was proven to be critical for promoting DLBCL cells proliferation by inhibiting ferroptosis. Mechanistically, ZHX2 binds to the promoter region of the solute carrier family 3-member 2 (SLC3A2) gene through liquid-liquid phase separation (LLPS) and activates its function to negatively regulate ferroptosis. Furthermore, we constructed lipid nanoparticles Zhx2-siRNA@LNP targeting DLBCL, which effectively inhibited the growth of the tumor in vivo. In summary, our study indicated that LLPS of ZHX2 protects DLBCL against ferroptosis through induction of SLC3A2, and disturbing it with Zhx2-siRNA@LNP could significantly repress DLBCL, providing a promising therapeutic strategy for DLBCL.
2025-07-30 | GSE292498 | GEO
Project description:Diffuse large B-cell lymphoma (DLBCL), the most common B-cell non-Hodgkin lymphoma (B-NHL), is characterized by strong aggression, high heterogeneity and poor prognosis. Consequently, there is an urgent need to identify crucial therapeutic targets. Here, we found that the transcription factor Zinc-finger and homeoboxes 2 (ZHX2) is highly expressed in DLBCL. Subsequently, ZHX2 was proven to be critical for promoting DLBCL cells proliferation by inhibiting ferroptosis. Mechanistically, ZHX2 binds to the promoter region of the solute carrier family 3-member 2 (SLC3A2) gene through liquid-liquid phase separation (LLPS) and activates its function to negatively regulate ferroptosis. Furthermore, we constructed lipid nanoparticles Zhx2-siRNA@LNP targeting DLBCL, which effectively inhibited the growth of the tumor in vivo. In summary, our study indicated that LLPS of ZHX2 protects DLBCL against ferroptosis through induction of SLC3A2, and disturbing it with Zhx2-siRNA@LNP could significantly repress DLBCL, providing a promising therapeutic strategy for DLBCL.
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Project description:Liquid-liquid phase separation of ZHX2 protects DLBCL cells against ferroptosis through induction of SLC3A2 [ChIP-seq]
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Project description:Liquid-liquid phase separation of ZHX2 protects DLBCL cells against ferroptosis through induction of SLC3A2 [RNA-seq]
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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.
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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.
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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.
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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.
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