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

描述（由申请人提供）：HIF 1a N-末端超乙酰化和异羟肟HDACi组蛋白脱乙酰酶抑制剂（HDACi）的抗癌机制显示出令人鼓舞的抗肿瘤活性。然而，介导抗肿瘤作用的机制仍不清楚，这阻碍了基于HDACi的疗法的临床设计的优化和癌症患者的治疗结果的改善。该提案的目的是研究基于异羟肟的HDACi的抗癌机制，涉及抑制缺氧诱导因子1 α（HIF 1a），这是一种负责血管生成和癌症发展的蛋白质。核心假设是：HDAC同工酶-HIF 1a轴的抑制介导了异羟肟酸-HDACi的抗肿瘤作用，因为特异性HDAC同工酶阻止了HIF 1a的超乙酰化;当这些HDAC同工酶被抑制时，HIF 1a在其N-末端被超乙酰化，这破坏了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HIF 1a、血管生成和肿瘤生长的新方法。提出了三个目标。目标1：我们将确定特定的赖氨酸残基，可以通过异羟肟-HDACi在HIF 1a的N-末端高度乙酰化和测试的假设，HIF 1a的N-末端高度乙酰化破坏HIF 1a的功能和稳定性。目标二：我们将确定HDAC同工酶，必须被抑制，以实现HIF 1a N-末端乙酰化和测试的假设，HIF 1a N-末端乙酰化水平是由多种HDAC同工酶调节。目标3：我们将通过测试破坏HDAC同工酶-HIF 1a轴可以抑制HIF 1a，并损害血管生成和肿瘤生长的假设，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，HIF 1a可以通过特定的HDAC同工酶调节，并将提供一个机制的理由，为什么一些HDACi可以抑制HIF 1a，但其他人不能。这些知识支持不同类型的HDACi在癌症和其他疾病中的治疗活性，其中HIF 1a在病因和病理学上受到牵连，并且对于选择正确类型的HDACi进行治疗至关重要。 公共卫生相关性：从这笔赠款中获得的知识将帮助我们更有效、更适当地使用当前的癌症疗法来治疗癌症患者。它还将指导我们设计和发现下一代抗癌药物。

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.