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HDAC2 in HDAC inhibitor-based therapy for CRC

基于 HDAC 抑制剂的 CRC 治疗中的 HDAC2

基本信息

批准号：
9066592
负责人：
JING HU
金额：
$ 31.96万
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：
2012
资助国家：
美国
起止时间：
2012-07-16 至 2018-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9066592
关键词：
APC gene Adenomatous Polyposis Coli Antineoplastic Agents ApcMin/+ mice Biological Biology Cell Nucleus Clinical Clinical Trials Colon Colon Carcinoma Colorectal Cancer Combined Modality Therapy Complex Cutaneous Cytoplasm Deacetylase Development Disease Event Future Genetic Glycogen (Starch) Synthase Goals HDAC2 gene Histone Acetylation Histone Deacetylase Histone Deacetylase Inhibitor Human Intestinal Mucosa Intestinal Polyps Intestines Knock-out Lead Licensing Lysine Malignant Neoplasms Malignant neoplasm of lung Mediating Metastatic/Recurrent Mucous Membrane Mus Mutation Nuclear Pathway interactions Patients Play Protein Isoforms Proteolysis Refractory Regulation Resistance Role Sampling Signal Transduction Small Intestines Solid Neoplasm T-Cell Lymphoma Testing Therapeutic Tissues United States Up-Regulation Vorinostat Work Xenograft Model adenoma antitumor effect base cancer cell clinical effect design functional loss in vivo knock-down novel novel drug combination overexpression resistance mechanism tissue culture tumor tumor progression tumor xenograft tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): Histone deacetylase inhibitors (HDACis) are a promising new class of anticancer drugs. Two HDACis are licensed by the United States FDA for the treatment of advanced cutaneous T-cell lymphoma. Although clinical trials with HDACis as monotherapy in solid tumors have not been successful, HDACi shows promise in combination therapy for patients with recurrent metastatic lung cancer, suggesting that the full therapeutic potential of current HDACis will probably be best realized through a combination with other anticancer agents. However, currently there is little information to direct the clinical use of HDACi in combination with other agents. As colorectal cancer (CRC) remains an essentially incurable disease, it is critical to identify mechanism of HDACi resistance that can lead to combination strategies that increase HDACi therapeutic potential in CRC. The overall goal of this project is to uncover the HDAC mechanism responsible for the limited efficacy of HDACi treatment in colorectal cancer. There are 18 HDACs in humans and these different HDACs are not redundant in their function. In CRC, one of the most cancer relevant HDACs is HDAC2. We have found that in CRC cells, HDAC2 knockdown enhances the anti-tumor effect of SAHA, whereas overexpression of HDAC2 confers resistance to SAHA treatment. These findings strongly suggest that HDAC2 influences HDACi sensitivity and contributes to refractoriness to HDACi therapy in CRC cells. But the underlying mechanism by which HDAC2 works remains undefined. Clinical evidence suggests that HDACi refractoriness may involve mechanisms independent of deacetylase inhibition. Intriguingly, we have discovered that HDAC2 possesses a deacetylase-independent sumoylation-promoting activity and promotes sumoylation of Gsk3¿ (a key component of Wnt signaling). Based on our preliminary results, we hypothesize that HDAC2 sumoylation-promoting activity contributes to HDACi refractoriness in CRC cells by upregulating the Wnt/¿-catenin pathway through enhancing Gsk3¿ sumoylation. In this proposal, we will determine the role of the Wnt/¿-catenin pathway in HDAC2-mediated refractoriness in HDACi therapy. We will then validate the role of HDAC2 sumoylation-promoting activity in HDACi sensitivity of CRC cells. Finally, we will dissect how HDAC2 upregulates the Wnt/¿-catenin pathway through enhancing Gsk3¿ sumoylation. The successful completion of this proposed study could reveal a possible cause of insensitivity to HDACi treatment in CRC.

说明书(申请人提供)：组蛋白脱乙酰酶抑制剂(HDACis)是一类很有前途的抗癌新药。两种HDACis被美国FDA批准用于治疗晚期皮肤T细胞淋巴瘤。尽管HDACis作为实体瘤单一疗法的临床试验尚未成功，但HDACi在复发转移性肺癌患者的联合治疗中显示出希望，这表明目前的HDACis的全部治疗潜力可能通过与其他抗癌药物的联合使用而最好地实现。然而，目前指导临床的信息很少。 HDACi与其他药物联合使用。由于结直肠癌(CRC)仍然是一种本质上无法治愈的疾病，因此确定HDACi耐药的机制至关重要，这种机制可以导致联合治疗增加HDACi在结直肠癌中的治疗潜力。该项目的总体目标是揭示导致HDACi治疗结直肠癌疗效有限的HDAC机制。人类有18个HDAC，这些不同的HDAC在功能上并不是多余的。在结直肠癌中，与癌症最相关的HDAC2是HDAC2。我们发现，在CRC细胞中，HDAC2基因敲除增强了SAHA的抗肿瘤作用，而HDAC2的过表达则使其对SAHA治疗产生抵抗。这些发现有力地表明，HDAC2影响HDACi的敏感性，并有助于在结直肠癌细胞中进行HDACi治疗。但HDAC2的基本工作机制仍未确定。临床证据表明，HDACi的难治性可能涉及独立于脱乙酰酶抑制的机制。有趣的是，我们发现HDAC2具有脱乙酰酶非依赖的总甲基化促进活性，并促进GSK3β(Wnt信号的关键成分)的总甲基化。根据我们的初步结果，我们假设HDAC2苏莫化促进活性通过促进GSK3苏莫化而上调Wnt/β-catenin途径，从而在结直肠癌细胞中参与HDACi难治性。在这项提案中，我们将确定Wnt/β-连环蛋白通路在HDAC2介导的HDACi治疗中的难治性中的作用。然后，我们将验证HDAC2苏莫化促进活性在结直肠癌细胞对HDACi敏感性中的作用。最后，我们将剖析HDAC2是如何通过促进GSK3β甲基化上调Wnt/β-catenin途径的。这项拟议研究的成功完成可能揭示结直肠癌患者对HDACi治疗不敏感的一个可能原因。