SENP6, a novel p53 negative regulator, is an important new player in cancer

SENP6 是一种新型 p53 负调节因子，是癌症中重要的新参与者

基本信息

批准号：
10418636
负责人：
Zhaohui Feng
金额：
$ 35.64万
依托单位：
RUTGERS BIOMEDICAL AND HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-07-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10418636
关键词：
ApcMin/+ mice Azoxymethane Binding Cancer Model Cells Cessation of life Chemical Agents Colorectal Colorectal Cancer Colorectal Neoplasms DNA Sequence Alteration Development Enzymes FASN gene Fatty Acids Genes Goals Growth Human Impairment Intestines Knock-in Mouse Knock-out Knockout Mice Lead MDM2 gene Maintenance Malignant Neoplasms Mediating Modeling Molecular Mutation PSMD10 gene Pathway interactions Peptide Hydrolases Pharmacology Play Prognosis RNA interference screen Regulation Role Sampling Signal Pathway Signal Transduction Sodium Dextran Sulfate TP53 gene Testing Tetanus Helper Peptide Therapeutic Therapeutic Intervention Tumor Suppression Ubiquitination United States Work anti-cancer base cancer cell cancer diagnosis cancer therapy cancer type colon tumorigenesis colorectal cancer treatment expectation in vivo inhibitor knock-down mouse model novel novel strategies novel therapeutic intervention overexpression small molecule subcutaneous targeted treatment tumor tumor growth tumor xenograft tumorigenesis ubiquitin-protein ligase

项目摘要

Abstract Tumor suppressor p53 plays a key role in tumor suppression. p53 function is frequently impaired in cancer by mutation or other mechanisms, such as overexpression of negative regulators for p53, which contributes greatly to tumorigenesis. Cancer cells often display increased de novo fatty acid (FA) synthesis, which is critical for continued growth and proliferation of cancer cells. Colorectal cancer (CRC) is the third most commonly diagnosed cancer and the third leading cancer death in the United States. Further understanding the molecular mechanisms for colorectal tumorigenesis will provide novel strategies for cancer therapy. To identify novel genes that are critical for CRC development, we performed a large-scale unbiased in vivo RNA interference screen, and identified SUMO-Specific Protease SENP6 as a novel gene critical for colorectal tumorigenesis. Currently, the role and its mechanism of SENP6 in colorectal tumorigenesis are unclear. Our preliminary studies showed that SENP6 is frequently overexpressed in CRC, and its overexpression is associated with poor prognosis in CRC. Our preliminary results further strongly suggest that SENP6 overexpression plays a critical role in promoting tumor growth in CRC through inhibition of p53 function and activation of FA synthesis in CRC cells. Based on our preliminary results, we hypothesize that SENP6 plays an unidentified and critical role in promoting tumorigenesis in CRC through inhibiting p53 function and promoting FA synthesis. The goal of this proposed study is to determine the role of SENP6 in colorectal tumorigenesis and its underlying mechanisms, and furthermore, to test the potential therapeutic intervention targeting CRC with SENP6 overexpression. We will test our hypothesis by following specific aims. Aim 1. To determine the role of SENP6 in colorectal tumorigenesis in mouse models. Aim 2. To determine the mechanisms by which SENP6 promotes colorectal tumorigenesis and the potential application of SENP6 in CRC therapy. Aim 2 has following 2 sub-aims. 2A) To test the hypothesis that SENP6 downregulates p53 to promote colorectal tumorigenesis. 2B) To determine the role and mechanism of SENP6 in FA synthesis in CRC and its contribution to colorectal tumorigenesis. We will further test whether pharmacological reactivation of p53 and inhibition of FA synthesis is a potential therapeutic strategy for CRC with SENP6 overexpression. It is our expectation that this proposed study will reveal the critical role and mechanism of SENP6 in colorectal tumorigenesis, and the results from this study will have the potential to lead to the development of novel targets and strategies for CRC therapy.

抽象的肿瘤抑制p53在肿瘤抑制中起关键作用。 p53功能经常受到癌症的损害突变或其他机制，例如p53负调节剂的过表达，这有助于肿瘤发生极大。癌细胞通常显示从头脂肪酸（FA）合成增加，这是癌细胞的持续生长和增殖至关重要。结直肠癌（CRC）是第三大的通常被诊断出癌症和美国第三次主要的癌症死亡。进一步的理解结直肠肿瘤发生的分子机制将为癌症治疗提供新的策略。到确定对CRC发育至关重要的新型基因，我们进行了大规模公正的体内RNA 干涉屏幕，并确定相当特异性蛋白酶SENP6是对结直肠癌至关重要的新基因肿瘤发生。当前，SENP6在结直肠肿瘤发生中的作用及其机制尚不清楚。我们的初步研究表明，SENP6在CRC中经常过表达，其过表达是与CRC的预后不良有关。我们的初步结果进一步强烈表明SENP6 通过抑制p53功能和 CRC细胞中FA合成的激活。根据我们的初步结果，我们假设SENP6播放通过抑制p53功能和促进FA合成。这项拟议的研究的目的是确定SENP6在结直肠上的作用肿瘤发生及其基本机制，以及测试潜在的治疗干预措施用SENP6过表达靶向CRC。我们将通过以下特定目标来检验我们的假设。目标1 确定SENP6在小鼠模型中结直肠肿瘤发生中的作用。目标2。确定 SENP6促进结肠直肠肿瘤发生的机制和Senp6在 CRC疗法。 AIM 2具有以下2个子Aim。 2a）检验了SENP6下调p53的假设促进结直肠肿瘤发生。 2b）确定SENP6在FA合成中的作用和机制 CRC及其对结直肠肿瘤发生的贡献。我们将进一步测试药理学重新激活 p53和FA合成的抑制是SENP6过表达的CRC的潜在治疗策略。我们期望这项拟议的研究将揭示SENP6在结直肠内的关键作用和机制肿瘤发生，这项研究的结果将有可能导致新的发展 CRC治疗的目标和策略。