VHL Substrate Transcription Factor ZHX2 As An Oncogenic Driver In Clear Cell Renal Cell Carcinoma
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA432414 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR6659782.fastq.gz | Fastqsanger.gz | |||
| SRR6659783.fastq.gz | Fastqsanger.gz | |||
| SRR6659784.fastq.gz | Fastqsanger.gz | |||
| SRR6659785.fastq.gz | Fastqsanger.gz | |||
| SRR6659786.fastq.gz | Fastqsanger.gz |
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Project description:Inactivation of the von Hippel-Lindau (VHL) E3 ubiquitin ligase protein is a hallmark of clear cell renal cell carcinoma (ccRCC). Identifying how pathways affected by VHL loss contribute to ccRCC remains challenging. We used a genome-wide in vitro expression strategy to identify proteins that bound VHL only when hydroxylated. Zinc fingers and homeoboxes 2 (ZHX2) was found as a VHL target and its hydroxylation allowed VHL to regulate its protein stability. Tumor cells from ccRCC patients with VHL loss-of-function mutations usually had increased ZHX2 amount and nuclear localization. Functionally, depletion of ZHX2 inhibited VHL-deficient ccRCC cell growth in vitro and in vivo. Mechanistically, integrated ChIP-Seq and microarray analysis showed that ZHX2 promoted NF-kB activation. These studies reveal ZHX2 as a potential therapeutic target for ccRCC.
2018-07-19 | GSE109953 | GEO
Project description:Inactivation of the von Hippel-Lindau (VHL) E3 ubiquitin ligase protein is a hallmark of clear cell renal cell carcinoma (ccRCC). Identifying how pathways affected by VHL loss contribute to ccRCC remains challenging. We used a genome-wide in vitro expression strategy to identify proteins that bind VHL when hydroxylated. Zinc fingers and homeoboxes 2 (ZHX2) was found as a VHL target, and its hydroxylation allowed VHL to regulate its protein stability. Tumor cells from ccRCC patients with VHL loss-of-function mutations usually had increased abundance and nuclear localization of ZHX2. Functionally, depletion of ZHX2 inhibited VHL-deficient ccRCC cell growth in vitro and in vivo. Mechanistically, integrated chromatin immunoprecipitation sequencing and microarray analysis showed that ZHX2 promoted nuclear factor κB activation. These studies reveal ZHX2 as a potential therapeutic target for ccRCC.
| S-EPMC6154478 | biostudies-literature
Project description:The von Hippel-Lindau (VHL) tumor suppressor is a substrate-defining component of E3 ubiquitin ligase complexes that target cellular substrates for proteasome-mediated degradation. VHL inactivation by mutation or transcriptional silencing is observed in most sporadic cases of clear cell renal cell carcinoma (ccRCC). VHL loss in ccRCC leads to constitutive stabilization of E3 ligase substrates, including hypoxia inducible factor α (HIFα). HIFα stabilization upon VHL loss is known to contribute to ccRCC development through transactivation of hypoxia-responsive genes. HIF-independent VHL targets have been implicated in oncogenesis, although those mechanisms are less well-defined than for HIFα. Using proximity labeling to identify proteasomal-sensitive VHL interactors, we identified retinoblastoma protein (pRb) as a novel substrate of VHL. Mechanistically, VHL interacts with pRb in a proteasomal-sensitive manner, promoting its ubiquitin-mediated degradation. Concordantly, VHL-inactivation results in pRb hyperstabilization. Functionally, loss of pRb in ccRCC led to increased cell death, transcriptional changes, and loss of oncogenic properties in vitro and in vivo. We also show that downstream transcriptional changes induced by pRb hyperstabilization may contribute to ccRCC tumor development. Together, our findings reveal a novel VHL-related pathway which can be therapeutically targeted to inhibit ccRCC tumor development.
2025-04-08 | GSE293447 | GEO
Project description:Clear cell renal cell carcinoma (ccRCC) is characterized by loss of tumor suppressor Von Hippel Lindau (VHL) function. VHL is the component of E3 ligase complex that promotes the ubiquitination and degradation of hypoxia inducible factor alpha (including HIF1alpha and HIF2alpha) and Zinc Fingers And Homeoboxes 2 (ZHX2). Our recent research showed that ZHX2 contributed to ccRCC tumorigenesis in a HIF independent manner. However, it remains unknown whether ZHX2 can be regulated through deubiquitination. Here we performed a deubiquitinase (DUB) cDNA library binding screen and identified USP13 as a novel DUB that bound ZHX2 and promoted ZHX2 deubiquitination. As a result, USP13 promoted ZHX2 protein stability in an enzymatically dependent manner and depletion of USP13 led to ZHX2 downregulation in ccRCC. Functionally, USP13 depletion led to decreased cell proliferation measured by 2-D colony formation and 3-D anchorage independent growth. USP was a critical effector on maintaining kidney tumorigenesis in an orthotopic xenograft model and its depletion led to both decreased primary kidney tumorigenesis and spontaneous lung metastasis. Our results suggest that USP13 is a potential new therapeutic target in ccRCC.
2022-07-27 | GSE186717 | GEO
Project description:VHL is the most frequently mutated gene in ccRCC.It functions via the oxygen-dependent ubiquitin-mediated degradation of hypoxia-inducible factor (HIF). The stabilization and hyperactivation of HIF1 play essential roles in tumorigenesis. This is a TMT based proteomics experiment aimed to investigate the functions of VHL in ccRCC systematically.
2023-01-05 | PXD012665 | Pride
Project description:Inactivation of the von Hippel-Lindau (VHL) E3 ubiquitin ligase protein is a hallmark feature of ccRCC, a clear cell renal cell carcinoma. However, elucidating how VHL loss drives ccRCC pathogenesis remains challenging. As the most abundant posttranscriptional modification of mRNA in eukaryotes, N6-methyladenine (m6A) is involved in the posttranscriptional regulation of mRNA molecules and has been found to play an important role in the biological process of tumorigenesis and cancer progression. Here, we show that VHL has a protein interaction with the m6A demethylase FTO, but does not perform the classical function of targeting FTO for ubiquitination degradation. Rather, VHL acts as an adapter that promotes CK2 phosphorylation of FTO, thereby regulating the enzymatic activity of FTO. MeRIP-Seq and RNA-seq sequencing analyses identified EGR1 as one of the FTO targets for VHL-deficient ccRCC cell survival. Mechanistically, FTO in ccRCC decreases the m6A level of EGR1 and inhibits EGR1 and P53 protein levels, thereby promoting ccRCC proliferation. In summary, our study identified FTO as a potential non-hypoxia inducible factor (HIF) classical substrate of VHL, highlighted the critical role of FTO in regulating m6A levels in ccRCC progression, and identified the CK2-FTO-EGR1-P53 regulatory axis as a potential target for the treatment of VHL-deficient ccRCC.
2025-08-08 | PXD053566 | Pride
Project description:In order to explore the biological function and molecular mechanism of ZHX2 in VSMCs,in this study, we overexpressed ZHX2 in primery VSMCs used chromatin immunoprecipitation sequencing (ChIP-seq) methods to systematically investigate the downstream targets of ZHX2.
2023-10-07 | GSE244563 | GEO
Project description:The liver has an exceptional capacity for regeneration which is crucial for maintaining liver function. Since transcriptional regulation of genes controlling metabolism and cell division is a hallmark of liver regeneration (LR), we investigated the role of Zinc-finger and homeboxes 2 (ZHX2), a transcription factor critical for regulating liver postnatal gene expression and hepatic lipid hemostasis, in LR. Our results show that hepatocyte-specific Zhx2 knockout (Zhx2-KOhep) enhances LR after 2/3 partial hepatectomy in mice. Proteomics assays revealed higher mitochondrial oxidative phosphorylation (OXPHOS) in Zhx2-KOhep mouse livers. Oxygen consumption rate (OCR) and ATP generation assays confirmed the enhanced OXPHOS in Zhx2-KOhep mouse livers and human hepatocytes with ZHX2 knockdown.
2023-10-17 | PXD027897 | Pride
Project description:Primary rat VSMCs were infected with Ad-Control and Ad-ZHX2 and stimulated with PDGF-BB of 24h. RNAseq and differential expression analysis were performed to investigate the role of ZHX2 in VSMCs.
2023-10-07 | GSE244564 | GEO
Project description:Inactivation of the E3 ubiquitin ligase protein von Hippel-Lindau (VHL) is critical to clear cell renal cell carcinomas (ccRCC) and VHL syndrome. VHL loss leads to stabilization of hypoxia-inducible factor α (HIFα) and other substrate proteins, which may drive various tumor-promoting pathways. This process is likely reversible, because even in the highly aggressive human VHL-deficient ccRCC cell line 786-O, restoring VHL expression almost completely abolishes orthotopic tumor formation in immuno-deficient mice. This result highlights the potential of treating ccRCC by re-expressing VHL with gene therapy. However, there is inadequate understanding of the consequence of VHL restoration at the molecular level. Here, we reinstalled VHL expression in 786-O and performed transcriptome, proteome and ubiquitome profiling to assess the molecular impact.
2021-10-18 | GSE186013 | GEO