权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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.

项目摘要肾透明细胞癌(CcRCC)约占所有肾癌的85%，是耐药的。可用于多种癌症疗法，具有极高的致命性。CcRCC的一个特点是冯·希佩尔的失活 Lindau(VHL)肿瘤抑制基因，该基因因突变或高甲基化而失活，高达90% Ccrcc。而pVHL作为E3泛素连接酶适配子蛋白发挥作用，促进低氧诱导因子(HIFα)转录因子，其他关键的pVHL底物现在才刚刚出现，它们的肾癌中的功能作用仍未确定。在这里，我们鉴定了一个锌指/同源域蛋白ZHX2 利用新开发的全基因组体外表达策略作为潜在的新型pVHL底物再加上GST结合筛选。我们的初步数据表明pVHL与之相互作用并降解 ZHX2以羟基酶活性依赖的方式，类似于对缺氧诱导因子α蛋白的调节。在功能上， ZHX2基因敲除可阻断pVHL基因缺陷的细胞增殖、软琼脂生长和移植瘤生长肾癌细胞。重要的是，ZHX2在ccRCC肿瘤中的表达水平显著高于正常的病人。在机制上，ZHX2与核因子-kB的RelA/p65亚基相互作用并正向调节 PVHL缺失诱导的relA/p65核定位。芯片序列和微阵列的综合分析也揭示了结论：ZHX2在肾细胞癌中既调节依赖于核因子-kB的通路，又调节独立的通路。因此，我们假设 ZHX2通过核因子-kB依赖和非依赖途径促进肾脏肿瘤的发生在VHL失活后。这是第一次针对ZHX2的致癌功能进行的研究，关注其在肾癌中pVHL缺失的下游的关键作用。在具体目标1中，我们将研究 PVHL以羟基化依赖的方式调控ZHX2的机制。在具体目标2中，我们将确定去调控的ZHX2在pVHL缺陷型肾癌中的功能意义。以特定的目标 3，我们将确定ZHX2调节NF-kB依赖和非依赖信号转导的机制和pVHL丢失后的肾脏肿瘤发生。这项提案的成功完成将提供重大的新的与绝大多数肾细胞癌相关的致癌机制的分子洞察以及这种典型的致命疾病可能有新的治疗方法。

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.