HDAC2 in Oncogenesis

HDAC2 在肿瘤发生中的作用

基本信息

批准号：
8843393
负责人：
JING HU
金额：
$ 16.75万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-05-01 至 2017-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8843393
关键词：
APC gene Adenomatous Polyposis Coli Agar Age ApcMin/+ mice Apoptosis Apoptotic Binding C-terminal Cancer Cell Growth Cancer Etiology Cell Culture Techniques Cell Nucleus Cell physiology Cells Colon Carcinoma Colorectal Cancer Cytoplasm DNA Sequence Alteration Deacetylase Development Disease Eukaryotic Initiation Factor-4E Gatekeeping Gene Targeting Genes Genetic Genetic Translation Glycogen (Starch) Synthase Growth Health Human Intervention Intestinal Mucosa Intestinal Neoplasms Intestinal Polyps Intestines Knock-out Link Malignant Neoplasms Manuscripts Mediating Molecular Mus Mutate Mutation Oncogenes Oncogenic Pathway interactions Pharmaceutical Preparations Play Property Protein Biosynthesis Publishing Regulation Risk Role Testing Tissues Translations Tumor Suppressor Genes Tumor Suppressor Proteins Ubiquitin Up-Regulation Validation Xenograft Model adenoma base cancer cell cancer initiation cancer risk cancer therapy carcinogenesis colon tumorigenesis design functional loss histone deacetylase 2 inhibitor/antagonist insight loss of function mutation mRNA capping mutant protein activation reconstitution research study targeted cancer therapy tool tumor tumor growth tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): About 85% of human colorectal cancers (CRCs) are associated with inactivation mutations of the tumor suppressor adenomatous polyposis coli (APC) gene. Loss-of-function mutations are generally not drug-able as it is difficult to restore a function that is lost, but understanding the molecular consequences of APC mutation and how they mechanistically link to CRC development could suggest new intervention approaches for this disease. Mice study indicates that one such consequence is the induction of HDAC2 (histone deacetylase 2) expression. HDAC2 is also elevated in human colon cancers, suggesting that APC mutation-mediated HDAC2 induction is a common feature seen in both APCmin/+ mice and human CRC. Genetic knockout of the endogenous HDAC2 diminishes adenoma formation in APCmin/+ mice, indicating the critical role of HDAC2 in intestinal tumorigenesis and strongly suggesting that targeting HDAC2 could be a promising approach for CRC treatment. Targeted cancer therapy relies on a thorough characterization and validation of the cancer target, but how HDAC2 acts to promote intestinal tumorigenesis remains unclear. The best known feature of HDACs is their deacetylase activity. Until now, the role of HDAC2 in cancer is solely attributed to its deacetylase activity. However, we have recently revealed that HDAC2 possesses a deacetylase-independent sumoylation-promoting activity. Based on our published evidence and preliminary results that HDAC2 promotes sumoylation of substrates with pivotal roles in human cancer, we hypothesize that HDAC2 sumoylation-promoting activity contributes to intestinal tumorigenesis. In this application, we will first conduct detailed characterization of the motifs required for HDAC2 sumoylation-promoting activity; we will then validate the functional role of HDAC2 sumoylation- promoting activity in both cell culture and in mice. Completion of the study will reveal information essential for the design and development of inhibitors that target HDAC2 sumoylation activity. The results of the proposed experiments could add new insights into intestinal tumorigenesis, with implication for alternative approach to treating APC-mutated CRC.

描述（由申请人提供）：约 85% 的人类结直肠癌 (CRC) 与抑癌腺瘤性结肠息肉病 (APC) 基因的失活突变有关。功能丧失性突变通常无法通过药物治疗，因为很难恢复丧失的功能，但了解 APC 突变的分子后果以及它们与 CRC 发展的机制联系可能会为这种疾病提出新的干预方法。小鼠研究表明，此类后果之一是诱导 HDAC2（组蛋白脱乙酰酶 2）表达。 HDAC2 在人类结肠癌中也升高，表明 APC 突变介导的 HDAC2 诱导是 APCmin/+ 小鼠和人类 CRC 中常见的特征。内源性 HDAC2 的基因敲除可减少 APCmin/+ 小鼠中腺瘤的形成，表明 HDAC2 在肠道肿瘤发生中的关键作用，并强烈表明靶向 HDAC2 可能是治疗 CRC 的一种有前途的方法。癌症靶向治疗依赖于对癌症靶标的彻底表征和验证，但 HDAC2 如何促进肠道肿瘤发生仍不清楚。 HDAC 最著名的特征是它们的脱乙酰酶活性。到目前为止，HDAC2 在癌症中的作用仅归因于其脱乙酰酶活性。然而，我们最近发现 HDAC2 具有不依赖于脱乙酰酶的苏酰化促进活性。基于我们发表的证据和初步结果，即 HDAC2 促进在人类癌症中发挥关键作用的底物的苏酰化，我们假设 HDAC2 苏酰化促进活性有助于肠道肿瘤的发生。在此应用中，我们将首先对 HDAC2 sumoylation 促进活性所需的基序进行详细表征；然后我们将验证 HDAC2 sumoylation 促进活性在细胞培养物和小鼠中的功能作用。该研究的完成将揭示设计和开发针对 HDAC2 sumoylation 活性的抑制剂所必需的信息。拟议实验的结果可以为肠道肿瘤发生提供新的见解，并为治疗 APC 突变的 CRC 提供替代方法。