Supplement to Support Research Training in HDAC11 and Cancer

项目摘要 组蛋白去乙酰化酶（HDACs）最初被发现是与遗传学相关的关键表观遗传调节因子。 广泛的癌症中。HDAC与其同名的脱乙酰酶活性最相关;它们 催化从赖氨酸残基上除去乙酰基，这通常使染色质缩合， 减少某些基因的表达。然而，越来越多的证据表明，许多HDAC表现出其他 酶功能如脱脂酰化酶活性。此外，HDAC已经被示出与 组蛋白以外的蛋白质; HDAC 11以前被证明与RNA剪接功能相互作用 机械.因此，HDAC的酶促机制和靶蛋白尚未完全了解。 在补充我们的父母R 01赠款旨在研究HDAC 11在淋巴瘤，我们努力 研究RNA剪接中HDAC 11去酰化。脱乙酰化可以指导蛋白质的定位， HDAC 11作为胞质脱乙酰酶比作为核脱乙酰酶更有效地发挥功能。 因此，我们的目标是鉴定HDAC 11在癌细胞中的近似蛋白，确定HDAC 11的功能， 去乙酰化，并鉴定响应HDAC 11破坏的可变剪接mRNA。拟议 这项工作将促进对HDAC 11在癌症基因调控中的理解，有助于增加对 HDAC功能的多样性，并可能为HDAC依赖性癌症治疗开辟新的途径。

Project Summary The histone deacetylaces (HDACs) are originally discovered as critical epigenetic regulators implicated in a wide range of cancers. HDACs are most associated with their namesake deacetylase activity; they catalyze the removal of acetyl groups from lysine residues, which typically condenses chromatin and decreases expression of certain genes. However, there is increasing evidence that many HDACs exhibit other enzymatic functions such as defatty-acylase activity. Additionally, HDACs have been illustrated to interact with proteins other than histones; HDAC11 was previously illustrated to functionally interact with RNA splicing machinery. Thus, the enzymatic mechanism(s) and target proteins of HDACs are not fully understood. In supplement to our Parent R01 grant aimed at studying HDAC11 in lymphoma, we strive to investigate HDAC11 defatty-acylation in RNA splicing. Defatty-acylation can direct the localization of proteins, and HDAC11 functions more efficiently as a cytosolic defatty-acylase than as a nuclear deacetylase. Therefore, our aim is to identify HDAC11 proximate proteins in cancer cells, pinpoint the function of HDAC11 defatty-acylation, and identify alternatively spliced mRNAs in response to HDAC11 disruption. The proposed work will advance understanding of HDAC11 in cancer gene regulation, contribute to growing knowledge of diverse HDAC functions, and potentially open new avenues for HDAC dependent cancer therapies.