Supplement to Support Research Training in HDAC11 and Cancer

项目摘要 组蛋白脱乙酰酶(HDAC)最初是作为关键的表观遗传调节因子被发现的。 在多种癌症中都有。HDAC与它们的同名脱乙酰酶活性最相关；它们 催化去除赖氨酸残基中的乙酰基，它通常浓缩染色质和 减少某些基因的表达。然而，越来越多的证据表明，许多HDAC展示了其他 酶的功能，如脂肪酰基酶的活性。此外，HDAC已被图解为与 组蛋白以外的蛋白质；HDAC11先前被证明与RNA剪接功能相互作用 机械设备。因此，HDACs的酶机制(S)和靶蛋白还不完全清楚。 为了补充我们的母公司R01基金，旨在研究淋巴瘤的HDAC11，我们努力 研究HDAC11在RNA剪接中的脱脂酰化作用。脱脂酰化可以指导蛋白质的定位， HDAC11作为胞质脱乙酰酶比作为核脱乙酰酶更有效地发挥作用。 因此，我们的目标是鉴定癌细胞中的HDAC11邻近蛋白，准确定位HDAC11的功能 脱脂-酰化，并识别响应HDAC11中断的选择性剪接mRNAs。建议数 这项工作将促进对HDAC11在癌症基因调控中的理解，有助于增长对 多种HDAC功能，并可能为HDAC依赖的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.