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

摘要 抑癌基因P53在肿瘤抑制中起关键作用。在癌症中，P53的功能经常受到损害 突变或其他机制，如P53负调控因子的过度表达，这对 极大地促进了肿瘤的发生。癌细胞通常表现出从头合成脂肪酸(FA)增加，这是 对癌细胞的持续生长和增殖至关重要。结直肠癌(CRC)排在第三位 通常被诊断为癌症，是美国第三大癌症死亡病例。进一步了解 结直肠癌发生的分子机制将为肿瘤的治疗提供新的策略。至 确定对结直肠癌发展至关重要的新基因，我们在体内进行了大规模的无偏向RNA 干扰筛选，鉴定相扑专一性蛋白水解酶SENP6为结直肠癌关键新基因 肿瘤发生学。目前，SENP6在大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在结直肠癌中经常过表达，其过表达是 与结直肠癌预后不良有关。我们的初步结果进一步有力地表明，SENP6 过表达通过抑制P53和P53在促进结直肠癌生长中起关键作用 激活大肠癌细胞中FA的合成。根据我们的初步结果，我们假设SENP6发挥作用 通过抑制P53功能和抑癌基因在促进结直肠癌发生中的作用 促进脂肪酸合成。这项拟议的研究的目标是确定SENP6在结直肠中的作用 肿瘤的发生及其潜在的机制，并进一步测试潜在的治疗干预 靶向SENP6过表达的结直肠癌。我们将通过以下具体目标来检验我们的假设。目标1.目标 确定SENP6在小鼠结直肠肿瘤发生中的作用。目标2.确定 SENP6促进结直肠癌发生的机制及在结直肠癌中的应用前景 CRC治疗。目标2有以下两个子目标。2a)检验SENP6下调P53以 促进结直肠肿瘤的发生。2b)确定SENP6在脂肪酸合成中的作用和机制 结直肠癌及其在结直肠癌发生中的作用。我们将进一步测试药理上的重新激活 抑制P53和抑制FA合成是治疗SENP6过表达的结直肠癌的一种潜在策略。 我们期望这项拟议的研究将揭示SENP6在结直肠中的关键作用和机制 肿瘤的发生，这项研究的结果将有可能导致小说的发展 结直肠癌治疗的目标和策略。

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.