Hypoxia induces SHMT2 to regulate cellular redox and epigenetics

缺氧诱导 SHMT2 调节细胞氧化还原和表观遗传学

基本信息

批准号：
8821835
负责人：
Jiangbin Ye
金额：
$ 10.44万
依托单位：
SLOAN-KETTERING INST CAN RESEARCH
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-08-05 至 2017-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8821835
关键词：
3-phosphoglycerate Address Affect Back Breast Melanoma Cancer Patient Carbon Catabolism Cell Death Cell Differentiation process Cell Proliferation Chromosomes Consumption DNA DNA Methylation DNA Modification Methylases Data Diagnosis Enzymes Epigenetic Process Equilibrium Gene Expression Regulation Generations Genes Genetic Transcription Glucose Glutathione Glutathione Disulfide Glycine Glycine Hydroxymethyltransferase Health Histones Homocysteine Homocystine Human Hypermethylation Hypoxia Link Malignant Neoplasms Mammalian Cell Metabolic Metabolic Pathway Metabolism Methylation Methylenetetrahydrofolate Dehydrogenase (NADP+)Methyltransferase Mitochondria Modification NADP Non-Essential Amino Acid Oncogenic Oxidation-Reduction Oxygen Pathway interactions Phosphoglycerate dehydrogenase Play Production Protein Isoforms RNA Interference Rattus Reaction Reactive Oxygen Species Regulation Reporting Repression Resistance Role S-Adenosylhomocysteine S-Adenosylmethionine Series Serine Solid Neoplasm Stress Subarachnoid Hemorrhage Testing Tetrahydrofolates Up-Regulation Warburg Effect Withdrawal Xenograft procedure aldehyde dehydrogenases base cancer cell cancer therapy cancer type carbene cofactor epigenetic regulation glucose production histone methylation hypoxia inducible factor 1 insight malignant breast neoplasm methyl group neuroblastoma cell novel novel therapeutic intervention outcome forecast overexpression research study targeted cancer therapy therapeutic target transcription factor tumor tumor growth tumor microenvironment tumor progression tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): An emerging hallmark of cancer is that malignant cells modulate metabolic pathways to promote cancer progression. Although a series of reports have demonstrated that the synthetic pathway of the non-essential amino acid serine is upregulated in cancer, it remains poorly understood that how serine catabolism contributes to cancer progression. My preliminary studies demonstrated that the mitochondrial enzyme serine hydroxymethyltransferase 2 (SHMT2) is overexpressed in many cancers via induction by a combination of hypoxia-inducible factors 1 (HIF-1) and Myc under hypoxia (low oxygen). Hypoxia is a common microenvironmental stress in solid tumor. Given that hypoxia contributes to tumor aggressiveness and resistance to cancer therapy, it is pressing to determine the possible role(s) of SHMT2 induction in tumor adaption to hypoxia. SHMT2 converts serine to glycine, with concurrent generation of one-carbon unit donor methylene-THF. I found that knockdown of SHMT2 enhanced cellular reactive oxygen species (ROS) level under hypoxia, indicating a novel role of SHMT2 in maintaining cellular redox balance upon hypoxic stress. In addition, repression of SHMT2 abolished DNA/histone hypermethylation stimulated by hypoxia, suggesting that one-carbon unit flux from SHMT2 may be critical for cellular methyltransferase activity, which contributes to epigenetic modification of chromosomes. Since Myc is required for the basal expression and hypoxic induction of SHMT2, it is critical to define the role of SHMT2-dependent DNA/histone hypermethylation in myc- dependent tumorigenesis. This enhanced methylation may correlate with the inability of neuroblastoma cells to activate lineage-specific genes involved in cellular differentiation. To address these issues, two Specific Aims are proposed: 1) Identify how hypoxia-induced SHMT2 regulates mitochondrial redox balance. 2) Define the role(s) of histone/DNA methylation regulated by SHMT2 under hypoxia. Through these proposed studies I hope to broaden the understanding of the metabolic regulation of redox control and epigenetic modification under hypoxia, and develop new therapeutic approaches targeting hypoxic cancer.

描述（由申请人提供）：癌症的一个新特征是恶性细胞调节代谢途径以促进癌症进展。尽管一系列报告表明非必需氨基酸丝氨酸的合成途径在癌症中上调，但人们对丝氨酸分解代谢如何促进癌症进展仍知之甚少。我的初步研究表明，在缺氧（低氧）条件下，通过缺氧诱导因子 1 (HIF-1) 和 Myc 的组合诱导，线粒体酶丝氨酸羟甲基转移酶 2 (SHMT2) 在许多癌症中过度表达。缺氧是实体瘤中常见的微环境应激。鉴于缺氧会导致肿瘤的侵袭性和对癌症治疗的抵抗力，因此迫切需要确定 SHMT2 诱导在肿瘤适应缺氧中的可能作用。 SHMT2 将丝氨酸转化为甘氨酸，同时生成一碳单位供体亚甲基-THF。我发现 SHMT2 的敲低增强了缺氧条件下的细胞活性氧 (ROS) 水平，表明 SHMT2 在缺氧应激下维持细胞氧化还原平衡方面具有新的作用。此外，SHMT2的抑制消除了缺氧刺激的DNA/组蛋白高甲基化，这表明来自SHMT2的一碳单位通量可能对细胞甲基转移酶活性至关重要，这有助于染色体的表观遗传修饰。由于 SHMT2 的基础表达和缺氧诱导需要 Myc，因此确定 SHMT2 依赖性 DNA/组蛋白高甲基化在 myc 依赖性肿瘤发生中的作用至关重要。这种增强的甲基化可能与神经母细胞瘤细胞无法激活参与细胞分化的谱系特异性基因有关。为了解决这些问题，提出了两个具体目标：1）确定缺氧诱导的 SHMT2 如何调节线粒体氧化还原平衡。 2) 定义缺氧条件下 SHMT2 调节组蛋白/DNA 甲基化的作用。通过这些拟议的研究，我希望扩大对缺氧条件下氧化还原控制和表观遗传修饰的代谢调节的理解，并开发针对缺氧癌症的新治疗方法。