HOIL-1/RBCK1 promotes p53 degradation in Renal cancer cells
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE119864 | GEO | 2019/03/28
REPOSITORIES: GEO
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Project description:HOIL-1/RBCK1 promotes p53 degradation in Renal cancer cells
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Project description:Renal cell carcinoma (RCC) accounts for approximately 3% of adult malignancies, and the incidence of RCC continues to rise worldwide. Although RCC can be treated with surgery at an early stages, the five-year survival rates have been observed to decline dramatically in patients with advanced disease. Most patients with RCC treated with cytotoxic or targeted drugs will develop resistance at some point during therapy. Thus, it is necessary to identify novel therapeutic targets for RCC. Here, we found that RANBP2-type and C3HC4-type zinc finger-containing 1 (RBCK1) expression was upregulated in human RCC samples. Analysis of multiple public databases revealed the correlation between RBCK1 expression and poor prognosis in RCC patients. Subsequently, we performed RBCK1 depletion experiments in RCC cells that severely affected the in vivo and in vitro proliferation of renal cancer cells. The effects of RBCK1 on cell proliferation could be rescued with p53 expression knockdown in two cell lines expressing wild-type p53. Further experiments demonstrated that RBCK1 could facilitate p53 poly-ubiquitination and degradation by direct interaction with p53. Together, our results show that RBCK1 may serve as a promising target for RCC therapy by restoring p53 functions.
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Project description:Despite the promise of targeted tyrosine kinase inhibitors (TKIs), such as sunitinib, in the extension of survival time in patients with clear cell renal cell carcinoma (ccRCC) progression or metastasis, the patients eventually succumb to inevitable drug resistance. Protein degradation executed by the ubiquitin-dependent proteasome system played an important role in determining the sensitivity of ccRCC to sunitinib. Here, we applied the bioinformatic analysis to identify that E3 ligase RBCK1 was elevated in the sunitinib-resistant renal cancer cell lines or patient specimens. The subsequent in vitro or in vivo studies demonstrated that RBCK1 contributed to decreasing the sensitivity of ccRCC to sunitinib. Then, we showed that inhibition of RBCK1 activated the AKT and MAPK signaling pathways, which might be one of the main reasons why RBCK1 induces sunitinib resistance in ccRCC cells. Mechanistically, our results indicated that RBCK1 promotes the degradation of ANKRD35 and that ANKRD35 destabilizes MITD1 by binding with SUMO2 in ccRCC cells. In addition, we showed that the RBCK1-ANKRD35-MITD1-ANXA1 axis regulates the phosphorylation of AKT and ERK and contributes to the dysregulation of sunitinib in ccRCC cells. Therefore, we identified a novel mechanism for regulating the sensitivity of sunitinib in ccRCC. Therefore, we elucidated a novel mechanism by which RBCK1 regulates sunitinib sensitivity in ccRCC.
2025-10-02 | GSE214635 | GEO
Project description:Triple negative breast cancer (TNBC) is one of the most lethal breast cancer subtypes. Due to a lack of effective therapeutic targets, chemotherapy is still the main medical treatment for TNBC patients. Thus, it is important and necessary to identify novel therapeutic targets for TNBC. Recent genomic studies implicated the hyper-activation of Hippo/YAP signaling in TNBC, manifesting its critical roles in TNBC carcinogenesis and cancer progression. RBCK1 was firstly identified as an important component for linear ubiquitin assembly complex (LUBAC) and facilitates NFKB signaling in immune response. Further studies showed RBCK1 also facilitated luminal type breast cancer growth and endocrine resistance via trans-activation estrogen receptor alpha. Interestingly, our data revealed an opposite function for RBCK1 in TNBC progression. RBCK1 over-expression inhibited TNBC cell progression in vitro and in vivo, while RBCK1depletion promoted TNBC cell invasion. The whole genomic expression profiling showed that RBCK1 depletion activated Hippo/YAP axis. RBCK1 depletion increased YAP protein level and Hippo target gene expression in TNBC. The molecular biology studies showed that RBCK1 could associate with YAP protein and enhance YAP protein stability via promoting YAP K48-linked poly-ubiquitination at several YAP lysine sites (K76, K204 and K321). Our study revealed the multi-faced RBCK1 function in different subtypes of breast cancer patients and a promising therapeutic target for TNBC treatment.
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Project description:RanBP2 type and C3HC4 type zinc finger containing protein 1 (RBCK1,) is a 58 kDa protein containing N-terminal ubiquitin like (UBL) domain, npl4 type zinc finger (NZF) domain and catalytic carbon terminal RBR domain. It is known that it has abnormal expression in tumors, making it a valuable diagnostic marker and drug target. A large number of studies have confirmed that in ER positive breast cancer, about 25%-40% of the tumor showed a visible hypoxia area. Under hypoxia, tumor cells can activate HIF1 pathway and widely activate the expression of downstream genes. Hypoxia inducible factor HIF-1 is composed of HIF-1α and HIF-1β Two subunits, The protein level of HIF-1α is precisely regulated by oxygen concentration. Here, we report RBCK1, a RING family ubiquitin ligase that regulates HIF1α, promoting ER positive breast cancer growth and inhibiting apoptosis. Deletion of RBCK1 inhibits ER positive breast cancer growth and promotes cell death. RNA sequencing analysis showed that in ER positive breast cancer, RBCK1 may be an important modifier of HIF1α signal pathway. Further experiments showed that RBCK1 and HIF1α Interacts and inhibits HIF1α polyubiquitination to inhibit HIF1α degradation in ER positive breast cancer cells. These finding reveals a novel direct HIF1α regulator and a potential therapeutic target for ER positive breast cancer.
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Project description:Loss-of-expression and loss-of-function mutations in HOIL1 (RBCK1) results in disruption of the linear ubiquitination assembly complex (LUBAC). Impairment of LUBAC results in impaired NF-kB activation in response to TNF and IL-1b in fibroblastic cells, but also display enhanced pro-inflammatory responses to TNF and IL-1b in leukocytes. Autosomal recessive complete human HOIL-1/RBCK1 deficiency is a new disorder with unbalanced cellular responses to pro-inflammatory cytokines, resulting in the paradoxical association of auto-inflammation and pyogenic bacterial disease, as well as the surprising development of muscular amylopectinosis. The genome-wide gene expression analysis showed that human HOIL-1 deficiency results in impaired NF-B activation in response to TNF- and IL-1 in fibroblastic cells.
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Project description:Streptozotocin induces renal proximal tubular injury through p53 signaling activation
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Project description:Clear cell renal cell carcinoma (ccRCC), the major subtype of RCC, is frequently diagnosed at late/metastatic stage with 13% 5-year disease-free survival. Functional inactivation of the wild type p53 protein is implicated in ccRCC therapy resistance, but the detailed mechanisms of p53 malfunction are still poorly characterized. Thus, a better understanding of mechanisms of disease progression and therapy resistance is required. Here, we report a novel ccRCC dependence on the promyelocytic leukemia PML protein. We show that PML is overexpressed in ccRCC and that PML depletion inhibits cell proliferation and relieves pathologic features of anaplastic disease in vivo. Mechanistically, PML loss unleashed p53-dependent cellular senescence thus depicting a novel regulatory axis to limit p53 activity and senescence in ccRCC. Treatment with the FDA-approved PML inhibitor arsenic trioxide induced PML degradation and p53 accumulation, and inhibited ccRCC expansion in vitro and in vivo. Therefore, by defining non-oncogene addiction to the PML gene, our work uncovers a novel ccRCC vulnerability and lays the foundation for repurposing an available pharmacological intervention to restore p53 function and chemosensitivity.
2024-04-23 | GSE246846 | GEO
Project description:HOX proteins define a family of key transcription factors regulating animal embryogenesis. HOX genes have also been linked to oncogenesis and HOXA1 has been described to be active in several cancers, including breast cancer. Through a proteome-wide interaction screening, we previously identified the TNFR-associated proteins RBCK1/HOIL-1 and TRAF2 as HOXA1 interactors suggesting that HOXA1 is functionally linked to the TNF/NF-κB signaling pathway. Here, we reveal a strong positive correlation between expression of HOXA1 and of members of the TNF/NF-κB pathway in breast tumor datasets. Functionally, we demonstrate that HOXA1 can activate NF-κB and operates upstream of the NF-κB inhibitor IκB. Consistently, we next demonstrate that the HOXA1-mediated activation of NF-κB is non-transcriptional and that RBCK1 and TRAF2 influences on NF-κB are epistatic to HOXA1. We also identify an 11 Histidine repeat and the homeodomain of HOXA1 to be required both for RBCK1 and TRAF2 interaction and NF-κB stimulation. Finally, we highlight that activation of NF-κB is crucial for HOXA1 oncogenic activity.
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Project description:The proteome of clinical tissue samples diagnosed with clear cell renal cell carcinoma (ccRCC) and papillary renal cell carcinoma (pRCC) were evaluated analyzed along with the dataset identifier PXD022018 to establish a potential discriminative biomarker panel of proteins for these tumors subtypes.
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