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HDAC10, Mitochondria and autophagy-a novel network targeted by HDAC inhibitors

HDAC10、线粒体和自噬——HDAC 抑制剂靶向的新型网络

基本信息

批准号：
7895482
负责人：
TSO-PANG YAO
金额：
$ 32.37万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-08-01 至 2011-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7895482
关键词：
Acetylation Affect Apoptosis Autophagocytosis Biochemical Biological Biological Process Cell Cycle Cell Death Cell Death Induction Cell Survival Cessation of life Clinic Complex Critical Pathways Deacetylase Development Family member Foundations Fractionation Future Grant Growth HDAC6 gene Histone Deacetylase Histone Deacetylase Inhibitor Knowledge Link Malignant Neoplasms Maps Mass Spectrum Analysis Mediating Membrane Potentials Metabolic stress Metabolism Mitochondria Molecular Nodal Organelles Oxygen Pathway interactions Phenotype Play Process Production Proteins Regulation Role Signal Pathway Technology Testing Therapeutic Transcriptional Regulation Tumor Suppression Vorinostat antitumor agent base biological adaptation to stress cancer cell cancer therapy cell growth combinatorial design human FRAP1 protein inhibitor/antagonist insight killings member neoplastic cell non-genomic novel programs research study response therapeutic target tumor

项目摘要

HDAC inhibitors (HDACI) are promising anti-tumor agents that have just entered the clinics. Despite their potent activity, the fundamental question of how HDAC inhibitors achieve their anti-tumor effects remains poorly understood. It is not known which of the HDAC family members or which cellular pathway is the most critical target for the antitumor activity of HDACI. This knowledge would facilitate the development of more effective inhibitors that target specific HDAC member(s) and identify the pathway(s) critical for HDACI to kill tumors, thereby aiding in the rational design of future cancer therapy. We have discovered that inactivation of a single HDAC member, HDAC10, recapitulates all major effects of HDACI, including growth arrest, cell death, induction of a cell cycle inhibitor, and reactive oxygen production (ROS). We further showed that HDAC10 inactivation and HDACI treatment both dramatically activate autophagy, a cellular response intimately linked to metabolic stress and cell death. These findings strongly suggest that HDAC10 is a key target mediating the anti-tumor activity of HDACI. Remarkably, we found that HDAC10 is localized to mitochondria. We hypothesize that HDACI elicits anti-tumor effects by targeting the mitochondrial deacetylase HDAC10, which controls mitochondrial function and autophagy important for tumor cell growth and proliferation. Specifically, we propose:

HDAC抑制剂（HDACI）是一种很有前景的抗肿瘤药物，刚刚进入临床。尽管它们具有强大的活性，但HDAC抑制剂如何实现其抗肿瘤作用的基本问题仍然知之甚少。目前尚不清楚HDAC家族的哪一个成员或哪一条细胞通路是HDAC抗肿瘤活性最关键的靶点。这一知识将有助于开发更有效的抑制剂，以特定的HDAC成员为目标，并确定HDACI杀死肿瘤的关键途径，从而有助于合理设计未来的癌症治疗。我们发现单个HDAC成员HDAC10的失活概括了HDACI的所有主要作用，包括生长停滞、细胞死亡、诱导细胞周期抑制剂和活性氧产生（ROS）。我们进一步表明，HDAC10失活和HDACI治疗均显著激活自噬，这是一种与代谢应激和细胞死亡密切相关的细胞反应。这些发现强烈提示HDAC10是介导HDACI抗肿瘤活性的关键靶点。值得注意的是，我们发现HDAC10定位于线粒体。我们假设HDACI通过靶向线粒体去乙酰化酶HDAC10引发抗肿瘤作用，HDAC10控制线粒体功能和自噬，对肿瘤细胞的生长和增殖很重要。具体而言，我们建议：