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GATA4 Ubiquitinated by CRL4B complex to stimulated Lysosome and promote Ovarian cancer EMT process [ChIP-seq]

ABSTRACT: GATA4 has emerged as a prominent transcription active factor for cardiomyogenesis and carcinogenesis. Ovarian cancer is a lethal cancer for women due to the hard diagnosis and easy metastasis. However, the role of GATA4 in breast cancer metastasis remains poorly understood. Here, we indicated that GATA4 was decreased in ovarian cancer and associated with excessive lysosome function and epithelial-mesenchymal transition (EMT). Mechanically, GATA4 was ubiquitinated by CUL4B, a submit of Cullin-Ring E3 ligase (CRL) complexes, and decreased the histone H3K27 acetylation. In vivo, knock down GATA4 was facilitated the proliferation and metastasis of SKOV3. RNA-seq and CUT&Tag ChIP-seq of the transcriptional target of the GATA4 and GATA4/CUL4B complex identified a cohort of genes including TRM22 and KLK15 that are potential involved in lysosome and EMT. These results suggest that GATA4 as a tumor suppressor to impair the lysosome acid environment and promote ovarian cancer metastasis in vivo and vitro through ubiquitin degradation system initiated by CRL4B complex. Our study supporting the tumor suppression role of GATA4, implied the pursuit of GATA4 as a therapeutic target for cancer intervention.

ORGANISM(S): Homo sapiens

PROVIDER: GSE260580 | GEO | 2026/01/07

REPOSITORIES: GEO

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Project description:Cullin 4B (CUL4B), a scaffold protein that assembles CRL4B ubiquitin ligase complexes, has been reported to be overexpressed in several types of solid tumors and contributes to epigenetic silencing of tumor suppressor. However, its clinical significance and the molecular mechanisms underlying its regulation in gastric cancer (GC) remain largely unknown. Here, we showed that CUL4B was elevated in GC tissues and its overexpression was positively correlated with poor prognosis and lymph node metastasis. CUL4B knockdown in GC cells decreased proliferation, mesenchymal transition and invasion in vitro, as well as tumor growth and metastasis in nude mice, and CUL4B overexpression induced the opposite results. Further studies showed that miR-101 could inhibit CUL4B expression by directly targeting its 3’-UTR and they were inversely correlated in clinical GC specimens. Notably, a positive relationship between CUL4B and HER2 was found in GC clinical specimens, GC cells and GC xenograft tumors. Through bioinformatics analysis of miRNA-seq data and target prediction, we nominated miR-125a as a direct target of CUL4B. ChIP assays demonstrated that CUL4B directly repressed miR-125a expression by physically binding to its promoter. In addition, we confirmed miR-125a is the target of HER2. Consequently, we demonstrated that CUL4B can up-regulate HER2 expression through repressing miR-125a. Most importantly, silencing of HER2 by Herceptin or siRNA partially reversed CUL4B-induced epithelial-to-mesenchymal transition (EMT), cell invasion and metastasis in vitro and in vivo. These findings define a CUL4B-miR-125a-HER2 regulatory mechanism shed light on CUL4B oncogenic mechanisms and reveals promising therapeutic targets for progressive GC. CUL4B proteins are frequently upregulated in human cancer, yet little is known about the underlying molecular mechanisms of CUL4B induced gastric cancer(GC) carcigenesis.Here, we uncover the critical role of CUL4B in gastric cancer growth and metastasis through the regulation of HER2 expression.CUL4B contributes to GC invasion and metastasis by transcriptional repression of HER2 targeting miR-125a, which provide a new insight into how CUL4B regulates GC progression and metastasis.

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GATA4 Ubiquitinated by CRL4B complex to stimulated Lysosome and promote Ovarian cancer EMT process [ChIP-seq]

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