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Exploration of ZHX2 as a novel substrate of pVHL and an oncogenic driver of renal cancer

探索 ZHX2 作为 pVHL 的新型底物和肾癌的致癌驱动因素

基本信息

批准号：
10246844
负责人：
Qing Zhang
金额：
$ 42.5万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-12-06 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10246844
关键词：
Accounting Adaptor Signaling Protein Address Agar Automobile Driving Binding CCL2 gene Cancer Patient Cancer cell line Cell Proliferation Cells ChIP-seq Chronic Clear cell renal cell carcinoma Conventional (Clear Cell) Renal Cell Carcinoma Coupled Cytotoxic Chemotherapy Data Development Disease Event Foundations Gene Expression Gene Targeting Genes Genomics Growth Homeodomain Proteins Hydroxylation Hypermethylation Hypoxia Hypoxia Inducible Factor IL8 gene In Vitro Kidney Kidney Neoplasms Literature Lymphoma Malignant Neoplasms Mediating Mixed Function Oxygenases Molecular Mutation NF-Kappa B p65 NF-kappa B Nuclear Oncogenes Oncogenic Oncoproteins Pathway interactions Patients Phenotype Primary carcinoma of the liver cells Process Procollagen-Proline Dioxygenase Prognosis Proline Proteins Regulation Renal Cell Carcinoma Renal carcinoma Reporting Resistance Role Signal Pathway Signal Transduction Site Specimen Transcription Repressor Tumor Suppressor Genes Tumor Suppressor Proteins Tumor Tissue Ubiquitination Up-Regulation Zinc Fingers cancer therapy genetic signature genome-wide inhibitor/antagonist innovation insight knock-down lipid metabolism mouse model novel novel therapeutic intervention novel therapeutics p65 prognostic value promoter screening transcription factor tumor tumor growth tumor xenograft tumorigenesis ubiquitin-protein ligase

项目摘要

Project Summary Clear cell renal cell carcinoma (ccRCC), which accounts for approximately 85% of all renal cancers, is resistant to a variety of cancer therapies and is highly lethal. A hallmark of ccRCC is the inactivation of the von Hippel Lindau (VHL) tumor suppressor gene, which is inactivated either by mutation or hypermethylation in up to 90% of ccRCC. While pVHL functions as an E3 ubiquitin ligase adaptor protein that promotes the degradation of hypoxia inducible (HIFα) transcription factors, other key pVHL substrates are only now emerging and their functional roles in renal cancer remains undefined. Here we identify a zinc-finger/homeodomain protein ZHX2 as a potential novel pVHL substrate by using a newly developed genome-wide in vitro expression strategy coupled with GST-binding screening. Our preliminary data suggests that pVHL interacts with and degrades ZHX2 in a hydroxylase activity-dependent manner, similar to regulation of the HIFα proteins. Functionally, knockdown of ZHX2 blocks cell proliferation, soft agar growth and xenograft tumor growth of pVHL-deficient renal cancer cells. Importantly, ZHX2 expression levels are strongly elevated in ccRCC tumors compared to normal patients. Mechanistically, ZHX2 interacts with the RelA/p65 subunit of NF-kB and positively regulates pVHL-loss induced RelA/p65 nuclear localization. Integrated analyses of ChIP-Seq and microarray also reveal that ZHX2 regulates both NF-kB-dependent and independent pathways in ccRCC. Therefore, we hypothesize that ZHX2 promotes renal oncogenesis through both NF-kB dependent and independent pathways following VHL inactivation. This is the first study directed at a pro-oncogenic function for ZHX2, with the focus on its key role downstream of the loss of pVHL in renal cancer. In Specific Aim 1, we will study the mechanism by which ZHX2 is regulated by pVHL in a hydroxylation-dependent manner. In Specific Aim 2, we will determine the functional significance of deregulated ZHX2 in pVHL-deficient renal cancer. In Specific Aim 3, we will determine the mechanisms by which ZHX2 regulates NF-kB-dependent and -independent signaling and renal tumorigenesis upon pVHL loss. Successful completion of this proposal would provide significant new molecular insight into oncogenic mechanisms associated with the great majority of ccRCC as well as the potential for new therapies for this typically lethal disease.

项目总结

项目成果

期刊论文数量（17）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

The von Hippel-Lindau Tumor Suppressor Gene: Implications and Therapeutic Opportunities.

DOI：
10.1097/ppo.0000000000000480
发表时间：
2020
期刊：
Cancer journal (Sudbury, Mass.)
影响因子：
0
作者：
通讯作者：

Hypoxia and Oxygen-Sensing Signaling in Gene Regulation and Cancer Progression.

DOI：
10.3390/ijms21218162
发表时间：
2020-10-31
期刊：
International journal of molecular sciences
影响因子：
5.6
作者：
Yang G;Shi R;Zhang Q
通讯作者：
Zhang Q

Optimized protocols for chromatin immunoprecipitation of exogenously expressed epitope-tagged proteins.

DOI：
10.1016/j.xpro.2023.102050
发表时间：
2023-03-17
期刊：
STAR PROTOCOLS
影响因子：
0
作者：
Fang, Wentong;Liao, Chengheng;Zhang, Qing
通讯作者：
Zhang, Qing

FBW7 Loss Promotes Chromosomal Instability and Tumorigenesis via Cyclin E1/CDK2-Mediated Phosphorylation of CENP-A.

DOI：
10.1158/0008-5472.can-17-1240
发表时间：
2017-09-15
期刊：
Cancer research
影响因子：
11.2
作者：
Takada M;Zhang W;Suzuki A;Kuroda TS;Yu Z;Inuzuka H;Gao D;Wan L;Zhuang M;Hu L;Zhai B;Fry CJ;Bloom K;Li G;Karpen GH;Wei W;Zhang Q
通讯作者：
Zhang Q

VHL and Hypoxia Signaling: Beyond HIF in Cancer.