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

• 批准号: 10197830
• 负责人: Zhaohui Feng
• 金额: $ 36.37万
• 依托单位: RBHS -CANCER INSTITUTE OF NEW JERSEY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-01 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10197830
• 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/antagonist; 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

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.

摘要 肿瘤抑制因子p53在肿瘤抑制中起着关键作用。p53功能在癌症中经常受到以下损害： 突变或其他机制，如p53负调控因子的过度表达， 对肿瘤的发生有很大的影响。癌细胞通常显示增加的从头脂肪酸（FA）合成，这是一种新的代谢途径。 对于癌细胞的持续生长和增殖至关重要。结直肠癌（CRC）是第三大 是美国常见的癌症，也是美国第三大癌症死亡原因。进一步理解 研究结直肠肿瘤发生的分子机制将为肿瘤的治疗提供新的策略。到 为了鉴定对CRC发展至关重要的新基因，我们进行了大规模的无偏体内RNA扩增， 干扰筛选，并确定SUMO特异性蛋白酶SENP6作为一个新的关键基因，结肠直肠癌 肿瘤发生目前，SENP 6在结直肠肿瘤发生中的作用及其机制尚不清楚。我们 初步研究表明，SENP 6在CRC中经常过表达，并且其过表达是 与结直肠癌预后不良相关。我们的初步结果进一步有力地表明，SENP6 过表达通过抑制p53功能在CRC中促进肿瘤生长中起关键作用， CRC细胞中FA合成的激活。根据我们的初步结果，我们假设SENP 6起作用， 通过抑制p53功能在CRC中促进肿瘤发生的未鉴定的关键作用， 促进FA合成。这项研究的目的是确定SENP 6在结直肠癌中的作用。 肿瘤发生及其潜在机制，并进一步测试潜在的治疗干预 用SENP 6过表达靶向CRC。我们将通过以下具体目标来检验我们的假设。目标1。到 确定SENP 6在小鼠模型中结肠直肠肿瘤发生中的作用。目标2.确定 SENP6促进结直肠肿瘤发生的机制以及SENP6在结直肠癌中的潜在应用 CRC治疗。目标2有以下两个子目标。2A）为了检验SENP6下调p53以使p53表达增加的假设， 促进结直肠肿瘤发生。2B）为了确定SENP 6在FA合成中的作用和机制， 结直肠癌及其对结直肠肿瘤发生的影响。我们将进一步测试药物激活是否 p53的表达和FA合成的抑制是SENP 6过表达的CRC的潜在治疗策略。 我们希望这项研究能够揭示SENP6在结直肠癌中的重要作用和机制。 肿瘤发生，本研究的结果将有可能导致新药物的开发 CRC治疗的目标和策略。