Identification of USP13 as a therapeutic target for ovarian cancer

项目摘要 癌症基因组图谱发现了人类卵巢癌(OVCA)基因组的突变 潜在地推动肿瘤的发生并改变细胞代谢以满足肿瘤的关键要求 细胞。虽然代谢酶的突变使新陈代谢与肿瘤的发生密切相关，但它们相对来说 在OVCA中很少见。更常见的情况是，新陈代谢的丰度和活性改变了癌症的新陈代谢。 酶通过泛素-蛋白酶体蛋白水解酶。我们应用生物信息学工具和荟萃分析 分析泛素-蛋白酶体蛋白分解中的基因，并确定它们与细胞的分子相互作用 新陈代谢。从我们的分析中发现的最显著的调节基因是泛素特异性的。 多肽酶13(USP13)。拟议的研究基于三个新的发现：1)深入分析 OVCA基因组中29.3%(158/538)发现USP13基因拷贝数增加 浆液性卵巢癌，但仅在3.7%的乳腺癌和0%的结直肠癌中，提示USP13 扩增是OVCA中一个独特而频繁的基因组事件；2)两个潜在的去泛素化靶点 在USP13中，三磷酸腺苷柠檬酸裂解酶(ACLY)和氧化戊二酸脱氢酶(OGDH)是关键的调节因子 测定谷氨酰胺分解、三羧酸循环和脂质合成；3)反应性代谢 肿瘤微环境中的基质细胞(TME)通过升高的谷氨酰胺合成代谢被重新编程 途径，它赋予基质细胞非典型的代谢灵活性和适应机制，允许它们 利用非正规来源的碳和氮在营养缺乏的情况下合成谷氨酰胺 卵巢条件下的TME。 尽管许多卵巢肿瘤对葡萄糖和谷氨酰胺的摄取增加，但 脂代谢升高，分子机制尚未确定，进展甚微。 以利用这些观察结果的潜在治疗用途。瓶颈是找到关键 驱动OVCA细胞新陈代谢的基因组改变。在这里，我们提出1)USP13扩增驱动 通过上调ACLY和OGDH的卵巢癌细胞代谢，以及2)一种合成致死方法 在OVCA中靶向PIK3CA和USP13，携带USP13扩增子，以获得理想的治疗结果。 我们将在三个目标中检验这些假设：目标1：确定USP13诱导的代谢 USP13扩增OVCA的改变；目的2：确定OVCA的分子机制 USP13活性的调节；目标3：利用人卵巢评估体内抑制USP13的效果 肿瘤模型。 USP13重组新陈代谢的能力和它的可药性激发了人们对靶向USP13和 OVCA中的肿瘤代谢，导致新的治疗方法的发展。

Project Summary The Cancer Genome Atlas has uncovered mutations in human ovarian cancer (OVCA) genomes that potentially drive tumorigenesis and alter cell metabolism to meet the crucial requirements of tumor cells. Whereas mutations in metabolic enzymes hardwire metabolism to tumorigenesis, they are relatively infrequent in OVCA. More often, cancer metabolism is altered by the abundance and activity of the metabolic enzymes through ubiquitin-proteasome proteolysis. We applied bioinformatic tools and meta-analysis to analyze genes in the ubiquitin-proteasome proteolysis and determined their molecular interactions with cell metabolism. The most significantly modulated gene identified from our analyses is ubiquitin specific peptidase 13 (USP13). The proposed studies are based on the three novel findings: 1) In-depth analysis of OVCA genomes identified copy number gains of USP13 gene in 29.3% (158 out of 538) of high- grade serous OVCA, but only in 3.7% of breast cancer and in 0% of colorectal cancer, suggesting that USP13 amplification is a unique and frequent genomic event in OVCA; 2) Two potential deubiquitination targets of USP13, ATP citrate lyase (ACLY) and oxoglutarate dehydrogenase (OGDH), are key regulators that determine glutaminolysis, tricarboxylic acid (TCA) cycle and lipid synthesis; 3) Metabolism of reactive stromal cells in tumor microenvironment (TME) is reprogrammed through an elevated glutamine anabolic pathway, which confers atypical metabolic flexibility and adaptive mechanisms in stromal cells, allowing them to harness carbon and nitrogen from noncanonical sources to synthesize glutamine in nutrient-deprived conditions in ovarian TME. Despite the fact that many ovarian tumors show increased uptake of glucose and glutamine and elevated lipid metabolism, no molecular mechanisms have been identified and little progress has been made towards harnessing the potential therapeutic use of these observations. The bottleneck is to find key genomic alterations that drives OVCA cell metabolism. Here, we propose that 1) USP13 amplification drives ovarian cancer cell metabolism by upregulating ACLY and OGDH, and 2) A synthetic lethal approach to target PIK3CA and USP13 in in OVCA harboring the USP13 amplicon for desirable therapeutic outcomes. We will test these hypotheses in three aims: Aim 1: To determine the USP13 induced metabolic alterations in OVCA with USP13 amplification; Aim 2: To determine molecular mechanisms for the regulation of USP13 activity; Aim 3: To assess the effects of USP13 inhibition in vivo using human ovarian tumor models. The ability of USP13 in rewiring metabolism and its druggability fuel the interest in targeting USP13 and cancer metabolism in OVCA, leading to the development of new therapeutics.