HIF1a N-terminus hyperacetylation and anticancer mechanism of hydroxamic-HDACi

描述（申请人提供）：羟肟类HDACi组蛋白去乙酰化酶抑制剂（HDACi）的HIF1a n端高乙酰化和抗癌机制显示出令人鼓舞的抗肿瘤活性。然而，其抗肿瘤作用的机制尚不清楚，这阻碍了基于HDACi的治疗方案的临床设计优化和癌症患者治疗效果的改善。本研究的目的是研究羟肟基HDACi的抗癌机制，包括抑制缺氧诱导因子1 α (HIF1a)，一种负责血管生成和癌症发展的蛋白质。中心假设是：HDAC同工酶-HIF1a轴的抑制介导羟肟-HDACi的抗肿瘤作用，因为特异性HDAC同工酶阻止HIF1a超乙酰化；当这些HDAC同工酶受到抑制时，HIF1a在其n端发生高乙酰化，从而破坏其转录活性和蛋白质稳定性。因此，鉴定和靶向这些特异性HDAC同工酶代表了抑制HIF1a、血管生成和肿瘤生长的新方法。提出了三个目标。目的1：我们将确定HIF1a n端可被羟肟- hdac超乙酰化的特定赖氨酸残基，并验证HIF1a n端超乙酰化破坏HIF1a功能和稳定性的假设。目的2：我们将确定为实现HIF1a n端超乙酰化而必须抑制的HDAC同工酶，并验证HIF1a n端乙酰化水平由多个HDAC同工酶调节的假设。目的3：我们将通过验证HDAC同工酶- HIF1a轴的破坏可以抑制HIF1a，并损害血管生成和肿瘤生长的假设，来确定体外和体内抑制特定HDAC同工酶的生物学后果。我们的建议将阐明一种新的机制，通过这种机制，HIF1a可以被特定的HDAC同工酶调节，并将为为什么一些HDAC可以抑制HIF1a而另一些不能提供机制上的理论依据。这一知识支持了不同类型HDACi在癌症和其他疾病中的治疗活动，其中HIF1a与病因和病理有关，对于选择正确类型的HDACi进行治疗至关重要。

DESCRIPTION (provided by applicant): HIF1a N-terminus hyperacetylation and the anticancer mechanism of hydroxamic HDACi Histone deacetylase inhibitors (HDACi) have shown encouraging antitumor activities. However, the mechanism mediating the antitumor effect is still unclear, which prevents the optimization of clinical designs of HDACi- based therapies and the improvement of treatment outcomes for patients with cancer. The goal of this proposal is to investigate the anticancer mechanism of hydroxamic-based HDACi involving the inhibition of hypoxia inducible factor 1 alpha (HIF1a), a protein responsible for angiogenesis and cancer development. The central hypothesis is: the inhibition of HDAC isozyme-HIF1a axis mediates the antitumor effect of hydroxamic -HDACi because specific HDAC isozymes prevent HIF1a hyperacetylation; and when these HDAC isozymes are inhibited, HIF1a is hyperacetylated at its N-terminus, which disrupts its transcriptional activity and protein stability. Therefore, identifying and targeting these specific HDAC isozymes represents a novel approach for suppressing HIF1a, angiogenesis, and tumor growth. Three aims are proposed. Aim 1: We will identify the specific lysine residues that can be hyperacetylated by hydroxamic-HDACi at the HIF1a N-terminus and test the hypothesis that HIF1a N-terminal hyperacetylation disrupts HIF1a function and stability. Aim 2: We will identify the HDAC isozymes that must be inhibited in order to achieve HIF1a N-terminal hyperacetylation and test the hypothesis that the HIF1a N-terminal acetylation level is regulated by multiple HDAC isozymes. Aim 3: We will determine the biological consequences of inhibiting specific HDAC isozymes in vitro and in vivo by testing the hypothesis that disruption of HDAC isozymes - HIF1a axis can inhibit HIF1a, and impair angiogenesis and tumor growth. Our proposal will elucidate a novel mechanism by which HIF1a can be regulated by specific HDAC isozymes and will provide a mechanistic rationale for why some HDACi can inhibit HIF1a, but others cannot. This knowledge underpins the therapeutic activities of different types of HDACi in cancer and other diseases where HIF1a is etiologically and pathologically implicated and is vital for selecting the right type of HDACi for therapy. PUBLIC HEALTH RELEVANCE: The knowledge gained from this grant will help us to use the current cancer therapeutics more effectively and appropriately to treat cancer patients. It will also guide us to design and discover the next generation of anticancer drugs.