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

• 批准号: 7580064
• 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
• 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/7580064
• 关键词: Acetylation; Applications Grants; Autophagocytosis; Biochemical; Biological; Cell Cycle; Cell Death; Cell Death Induction; Clinic; Critical Pathways; Deacetylase; Development; Family member; Fractionation; Future; Growth; Histone Deacetylase; Histone Deacetylase Inhibitor; Histones; Knowledge; Link; Malignant Neoplasms; Mediating; Membrane Potentials; Metabolic; Metabolic stress; Metabolism; Mitochondria; Nodal; Oncogenic; Organelles; Oxygen; Pathway interactions; Phenotype; Play; Process; Production; Regulation; Role; Signal Transduction; Testing; Therapeutic; Transcriptional Regulation; Vorinostat; antitumor agent; base; biological adaptation to stress; cancer cell; cancer therapy; cell growth; combinatorial; design; inhibitor/antagonist; insight; killings; member; neoplastic cell; novel; research study; response; therapeutic target; tumor

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）是刚刚进入临床的有前途的抗肿瘤药物。尽管 HDAC 抑制剂具有强大的活性，但人们对 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。目前尚不清楚哪个 HDAC 家族成员或哪个细胞途径是 HDACI 抗肿瘤活性的最关键靶标。这些知识将促进针对特定 HDAC 成员的更有效抑制剂的开发，并确定 HDACI 杀死肿瘤的关键途径，从而有助于未来癌症治疗的合理设计。我们发现，单个 HDAC 成员 HDAC10 的失活概括了 HDACI 的所有主要影响，包括生长停滞、细胞死亡、细胞周期抑制剂的诱导和活性氧产生 (ROS)。我们进一步表明，HDAC10 失活和 HDACI 治疗都能显着激活自噬，这是一种与代谢应激和细胞死亡密切相关的细胞反应。这些发现强烈表明 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 通过靶向线粒体脱乙酰酶 HDAC10 来引发抗肿瘤作用，该酶控制对肿瘤细胞生长和增殖至关重要的线粒体功能和自噬。具体来说，我们建议：