Genome-wide Screening Identifies SFMBT1 as an Oncogenic Driver in Cancer with VHL Loss
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA593996 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR10601430.fastq.gz | Fastqsanger.gz | |||
| SRR10601431.fastq.gz | Fastqsanger.gz | |||
| SRR10601432.fastq.gz | Fastqsanger.gz | |||
| SRR10601433.fastq.gz | Fastqsanger.gz | |||
| SRR10601434.fastq.gz | Fastqsanger.gz |
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Project description:von Hippel-Lindau (VHL) is a critical tumor suppres- sor in clear cell renal cell carcinomas (ccRCCs). It is important to identify additional therapeutic targets in ccRCC downstream of VHL loss besides hypox- ia-inducible factor 2a (HIF2a). By performing a genome-wide screen, we identified Scm-like with four malignant brain tumor domains 1 (SFMBT1) as a candidate pVHL target. SFMBT1 was considered to be a transcriptional repressor but its role in cancer remains unclear. ccRCC patients with VHL loss-of- function mutations displayed elevated SFMBT1 pro- tein levels. SFMBT1 hydroxylation on Proline residue 651 by EglN1 mediated its ubiquitination and degra- dation governed by pVHL. Depletion of SFMBT1 abolished ccRCC cell proliferation in vitro and in- hibited orthotopic tumor growth in vivo. Integrated analyses of ChIP-seq, RNA-seq, and patient prog- nosis identified sphingosine kinase 1 (SPHK1) as a key SFMBT1 target gene contributing to its onco- genic phenotype. Therefore, the pVHL-SFMBT1- SPHK1 axis serves as a potential therapeutic avenue for ccRCC
2020-02-04 | GSE141577 | GEO
Project description: Not available
| S-EPMC7093231 | biostudies-literature
Project description:VHL Substrate Transcription Factor ZHX2 As An Oncogenic Driver In Clear Cell Renal Cell Carcinoma
| PRJNA432414 | ENA
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: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:Altered metabolism is an important part of malignant transformation of tumor cells. Oncogenic transformation may reprogram tumor metabolism and render tumor cells addicted to extracellular nutrients. Such nutrient addictions associated with oncogenic mutations may offer therapeutic opportunities; however, it remains difficult to predict these nutrient addictions. Here, we performed a nutrigenetic screen to determine the phenotypes of isogenic pairs of clear-cell renal cancer cells (ccRCC) with or without VHL upon the deprivation of individual amino acids. We identified that cystine deprivation triggered rapid programmed necrosis in VHL-deficient RCC, but not in their VHL-restored counterparts. Similar cystine addiction was also observed in VHL-deficient primary RCC tumors cells. Blockage of cystine uptake significantly delayed xenograft growth of ccRCC. Importantly, cystine deprivation triggered similar metabolic changes regardless of VHL status. Therefore, metabolic differences due to cystine deprivation are not different enough to readily explain the distinct fate of life vs. death in VHL-deficient and restored cell.. Instead, we found that increased levels of TNFα associated with VHL loss in the VHL-deficient RCC force them to rely on intact RIPK1 to inhibit apoptosis. However, this pre-existing elevated TNFα in the VHL-deficient ccRCC renders these cells susceptible to the necrosis signaling triggered by cystine deprivation. In addition, we identified that cystine-deprived necrosis in VHL-deficient RCC depends on reciprocal amplification of the Src-p38-Noxa signaling and TNFα-RIP1/3-MLKL necrosis pathways that culminate in MLKL oligomerization and programmed necrosis. Together, our data reveal that the contextual cystine-addictions in VHL-deficient ccRCC is dependent on activating pre-existing oncogenic pathways to trigger programmed necrosis. RNA was extracted by RNAeasy kits (Qiagen) from the RCC4 Vec and VHL-reconstituted cells which were exposed to the control full DMEM or cystine deprived DMEM media for 6 hours (three replicates in each condition).
2016-07-01 | E-GEOD-60422 | biostudies-arrayexpress
Project description:VHL has been known as a tumour suppressor gene, also is an essential gene for some proteolysis-targeting chimera (PROTAC) degraders. Here by using CRISPR-cas9 genome wide screening we find that VHL mutation results in strong proliferation defect by HIF1A . VHL MUT shows malfunction of mitochondria which can be restored by HIF1A inhibition. VHL MUT bear specific genetic vulnerabilities which are druggable and mainly HIF1A dependent. In OE33 and MCF7, additional HIF1A inhibition on VHL MUT allows a complete ARV-771 drug resistance acquisition. Our study reports the consequence of VHL mutation and HIF1A dependent druggable genetic vulnerabilities in VHL mutant renal epithelial cells and possible PROTAC resistance acquisition mechanism in breast and oesophageal cancers, provides potential therapeutic targets and strategies for early precancerous and established cancerous cells.
2025-11-05 | GSE213241 | GEO
Project description:Altered metabolism is an important part of malignant transformation of tumor cells. Oncogenic transformation may reprogram tumor metabolism and render tumor cells addicted to extracellular nutrients. Such nutrient addictions associated with oncogenic mutations may offer therapeutic opportunities; however, it remains difficult to predict these nutrient addictions. Here, we performed a nutrigenetic screen to determine the phenotypes of isogenic pairs of clear-cell renal cancer cells (ccRCC) with or without VHL upon the deprivation of individual amino acids. We identified that cystine deprivation triggered rapid programmed necrosis in VHL-deficient RCC, but not in their VHL-restored counterparts. Similar cystine addiction was also observed in VHL-deficient primary RCC tumors cells. Blockage of cystine uptake significantly delayed xenograft growth of ccRCC. Importantly, cystine deprivation triggered similar metabolic changes regardless of VHL status. Therefore, metabolic differences due to cystine deprivation are not different enough to readily explain the distinct fate of life vs. death in VHL-deficient and restored cell.. Instead, we found that increased levels of TNFα associated with VHL loss in the VHL-deficient RCC force them to rely on intact RIPK1 to inhibit apoptosis. However, this pre-existing elevated TNFα in the VHL-deficient ccRCC renders these cells susceptible to the necrosis signaling triggered by cystine deprivation. In addition, we identified that cystine-deprived necrosis in VHL-deficient RCC depends on reciprocal amplification of the Src-p38-Noxa signaling and TNFα-RIP1/3-MLKL necrosis pathways that culminate in MLKL oligomerization and programmed necrosis. Together, our data reveal that the contextual cystine-addictions in VHL-deficient ccRCC is dependent on activating pre-existing oncogenic pathways to trigger programmed necrosis.
2016-07-01 | GSE60422 | GEO
Project description:Background: PTEN loss contributes to the development of many cancers and is associated with both hepatocellular carcinoma and cholangiocarcinoma. The pathogenesis of these malignancies is unclear, but they are speculated to arise from common cellular origins. We explored the influence of secondary effects, like hypoxia signaling, through co-deletion of Pten and Vhl in a murine model.Methods: We used a CreER-linked keratin 18 mouse model to conditionally delete Pten, Vhl or both, evaluating the resultant tumors by histology and gene expression microarray. A cohort of human cholangiocarcinoma samples was evaluated for relationships between HIF-1a expression and clinical outcomes.Results: Both Pten deletion genotypes developed liver tumors, but with differing phenotypes. Pten deletion alone led to large, invasive tumors with widespread hepatosteatosis. Co-deletion of Pten and Vhl resulted in low tumor burden and reduced steatosis. Microarray analysis divided mouse tumors’ respective genotypes by gene expression. This gene expression profile grouped a human tumor cohort according to histologic type with the Pten deletion signature aligning with hepatocellular carcinoma, whereas the Pten; Vhl deletion signature associated with cholangiocarcinomas. In a human cholangiocarcinoma cohort, we observed correlation between HIF-1a expression and overall survival.Conclusions: Pten deletion leads to tumor formation and steatosis in mouse livers. Co-deletion of Vhl and Pten resulted in lower tumor burden with gene expression profiling suggesting a switch from hepatocellular expression features to an expression profile more consistent with cholangiocarinoma. A possible relation between HIF-1a expression and increased overall survival in human cholangiocarcinoma suggests that hypoxia signaling influences tumor phenotype. reference x sample
2014-10-31 | E-GEOD-55874 | biostudies-arrayexpress
Project description:Clear cell renal cell carcinoma (ccRCC) is an aggressive disease characterized by dysregulated hypoxia signaling, metabolic defects, and a complex tumor microenvironment (TME) highly enriched in lymphoid and myeloid immune cells. Loss of the oxygen sensing gene, von Hippel Lindau (VHL), is a critical early event in ccRCC pathogenesis and promotes stabilization of hypoxia inducible factors (HIF) that upregulate pro-growth signaling pathways, including angiogenesis and aerobic glycolysis. However, whether VHL loss in cancer cells impacts the composition, metabolism, or function of immune cells in the TME remains unclear. Using Vhl wildtype (WT) and knockout (KO) in vivo murine kidney cancer models, we found that Vhl KO tumors were less proliferative and more infiltrated by immune cells. Tumor-associated macrophages (TAM) demonstrated enhanced proinflammatory transcriptional signatures from Vhl deficient tumors, and intratumoral myeloid cells residing in the Vhl KO TME showed increased in vivo glucose consumption. Vhl loss did not confer increased in vivo glucose uptake in cancer cells or lymphocytes, or detectable changes in metabolites in the interstitial fluid. Mechanistically, enhanced secretion of the chemokine, CX3CL1, was observed in Vhl KO cancer cells and its cognate receptor, CX3CR1, was significantly elevated on myeloid cells residing in the TME of Vhl deficient tumors. Human ccRCC tumors exhibit high expression of CX3CL1 and CX3CR1 as well as enhanced myeloid metabolism and proinflammatory properties. Here, we identify the importance of cancer cell-specific genetic features to drive environmental reprograming and shape the tumor immune landscape and identify a potential therapeutic target in the treatment of ccRCC.
2024-04-17 | GSE239889 | GEO