Identification of USP13 as a therapeutic target for ovarian cancer

鉴定 USP13 作为卵巢癌的治疗靶点

• 批准号: 10328885
• 负责人: Xiongbin Lu
• 金额: $ 34.75万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-02-02 至 2023-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10328885
• 关键词: AKT Signaling Pathway; ATP Citrate (pro-S)-Lyase; Automobile Driving; Binding; Carbon; Cell Proliferation; Cellular Metabolic Process; Citric Acid Cycle; Clinical Trials; Colorectal Cancer; Communication; Cysteine; DNA Sequence Alteration; Deubiquitination; Development; Enzymes; Event; Genes; Genomics; Glucose; Glutamine; Human; In Vitro; Ketoglutarate Dehydrogenase Complex; Lead; Link; Lipids; Malignant Neoplasms; Malignant neoplasm of ovary; Mediating; Meta-Analysis; Metabolic; Metabolism; Modeling; Molecular; Mutation; Nature; Nitrogen; Nucleotides; Nutrient; Oxides; PI3K/AKT; PIK3CA gene; Pathway interactions; Patients; Peptide Hydrolases; Phase; Phosphorylation; Post-Translational Protein Processing; Production; Proteolysis; Proto-Oncogene Proteins c-akt; Publishing; Regulation; Role; Serous; Source; Stromal Cells; Supporting Cell; Testing; The Cancer Genome Atlas; Therapeutic Uses; Tumor Tissue; Tumor-Derived; Ubiquitin; Xenograft procedure; base; bioinformatics tool; cancer cell; cancer genome; cell stroma; clinically relevant; design; flexibility; glucose uptake; in vivo; inhibitor; interest; knock-down; lipid metabolism; malignant breast neoplasm; mouse model; multicatalytic endopeptidase complex; nanoliposome; neoplastic cell; new therapeutic target; novel; novel therapeutics; ovarian neoplasm; overexpression; siRNA delivery; therapeutic target; therapy outcome; tumor; tumor metabolism; tumor microenvironment; tumor progression; tumor xenograft; tumorigenesis

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.

项目摘要 癌症基因组图谱揭示了人类卵巢癌（OVCA）基因组的突变 潜在地驱动肿瘤发生并改变细胞代谢以满足肿瘤生长的关键需求。 细胞而代谢酶突变硬连线代谢肿瘤发生，他们是相对 在OVCA中不常见。更常见的是，癌症代谢被代谢产物的丰度和活性改变， 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-蛋白酶体蛋白水解中的基因，并确定它们与细胞的分子相互作用 新陈代谢.从我们的分析中确定的最显著的调节基因是泛素特异性的 肽酶13（USP 13）。本研究基于以下三个新发现：1）深入分析 的OVCA基因组在29.3%（538个中的158个）的高分化卵巢癌中鉴定出USP 13基因拷贝数增加。 浆液性OVCA，但仅在3.7%的乳腺癌和0%的结直肠癌中，这表明USP 13 扩增是OVCA中独特且频繁的基因组事件; 2）两个潜在的去泛素化靶点 ATP柠檬酸裂解酶（ACLY）和酮戊二酸脱氢酶（OGDH）是关键的调节剂， 测定三羧酸（TCA）循环和脂质合成; 3）反应性代谢 肿瘤微环境（TME）中的基质细胞通过升高的谷氨酰胺合成代谢 途径，赋予基质细胞非典型的代谢灵活性和适应机制， 利用非典型来源的碳和氮来合成谷氨酰胺， 卵巢TME的条件。 尽管许多卵巢肿瘤显示葡萄糖和谷氨酰胺的摄取增加， 脂质代谢升高，尚未确定分子机制，进展甚微 利用这些观察结果的潜在治疗用途。瓶颈是找到钥匙 基因组改变驱动OVCA细胞代谢。在这里，我们建议1）USP 13放大驱动 通过上调ACLY和OGDH的卵巢癌细胞代谢，和2）一种合成致死方法， 靶向含有USP 13扩增子的OVCA中的PIK 3CA和USP 13，以获得理想的治疗结果。 我们将在三个目标中测试这些假设：目标1：确定USP 13诱导的代谢 USP 13扩增的OVCA改变;目的2：确定 目的3：使用人卵巢癌细胞评估USP 13抑制在体内的作用 肿瘤模型 USP 13在重新布线代谢中的能力及其可药用性激发了对靶向USP 13的兴趣， OVCA中的癌症代谢，导致新疗法的开发。

项目成果

Heterozygous deletion of chromosome 17p renders prostate cancer vulnerable to inhibition of RNA polymerase II.

• DOI: 10.1038/s41467-018-06811-z
• 发表时间: 2018-10-22
• 期刊: Nature communications
• 影响因子: 16.6
• 作者: Li Y;Liu Y;Xu H;Jiang G;Van der Jeught K;Fang Y;Zhou Z;Zhang L;Frieden M;Wang L;Luo Z;Radovich M;Schneider BP;Deng Y;Liu Y;Huang K;He B;Wang J;He X;Zhang X;Ji G;Lu X
• 通讯作者: Lu X

USP13 promotes development and metastasis of high-grade serous ovarian carcinoma in a novel mouse model.

• DOI: 10.1038/s41388-022-02224-x
• 发表时间: 2022-03
• 期刊: Oncogene
• 影响因子: 8
• 作者: Kwon J;Choi H;Ware AD;Morillo BC;Wang H;Bouker KB;Lu X;Waldman T;Han C
• 通讯作者: Han C

An organoid-based screen for epigenetic inhibitors that stimulate antigen presentation and potentiate T-cell-mediated cytotoxicity.

基于器官的表观遗传学抑制剂，刺激抗原表现并增强T细胞介导的细胞毒性。

• DOI: 10.1038/s41551-021-00805-x
• 发表时间: 2021-11
• 期刊: Nature biomedical engineering
• 影响因子: 28.1
• 作者: Zhou Z;Van der Jeught K;Fang Y;Yu T;Li Y;Ao Z;Liu S;Zhang L;Yang Y;Eyvani H;Cox ML;Wang X;He X;Ji G;Schneider BP;Guo F;Wan J;Zhang X;Lu X
• 通讯作者: Lu X