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

HDAC抑制剂(HDACi)是刚刚进入临床的很有前途的抗肿瘤药物。尽管它们具有很强的活性，但HDAC抑制剂如何实现其抗肿瘤作用的根本问题仍然知之甚少。目前尚不清楚哪些HDAC家族成员或哪种细胞途径是HDACi抗肿瘤活性的最关键靶点。这些知识将有助于开发更有效的靶向特定HDAC成员(S)的抑制剂，并确定HDACi杀死肿瘤的关键途径(S)，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、诱导细胞周期抑制物和活性氧产生(ROS)。我们进一步表明，HDAC10灭活和HDACi治疗都极大地激活了自噬，这是一种与代谢应激和细胞死亡密切相关的细胞反应。这些发现有力地表明，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产生抗肿瘤作用，该酶控制线粒体功能和自噬，对肿瘤细胞的生长和增殖至关重要。具体来说，我们建议：

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: