Role of UBR7, a novel H2BK120 E3 ubiquitin ligase, in suppression of breast cancer

摘要 三阴性乳腺癌(TNBC)是最具侵袭性的乳腺癌亚型，没有靶向治疗。 可用。尽管我们在这种疾病的基因驱动因素方面取得了巨大的进步，但我们 对导致乳房特定分子亚型的表观基因组改变的了解有限 癌症。表观基因组由一系列染色质修饰组成，它们共同形成一个动态的 染色质状态，影响对维持细胞特性至关重要的基因表达网络。 因此，特定的表观基因组改变可能是不同分子表型的驱动因素，然而我们 对特定的染色质模式如何与特定的分子相关联的了解有限 基底样乳腺癌等征象。由于表观遗传酶具有靶向性和表观遗传性 过程在本质上是可逆的，它们可能被证明是新治疗策略的极好靶点 针对特定的分子表型。我们的初步数据表明，UBR7具有肿瘤抑制活性 新式组蛋白修饰剂，用于三阴性乳腺癌。我们发现UBR7作为一种E3泛素连接酶 组蛋白H_2B在K120残基上的单素化，可能在转录上调节分子信号 浸润性乳腺癌。这些数据为深入描述肿瘤抑制因子提供了理论基础。 UBR7的功能和UBR7缺失带来的治疗脆弱性的识别。我们的假设是 UBR7在三重阴性乳腺中是一种有效的肿瘤抑制因子，并在三重阴性乳腺中促进侵袭行为 阴性乳腺癌部分是通过钙粘素途径调节的。这项提议的目的是首先 使用小鼠模型对UBR7肿瘤抑制活性进行深入表征，阐明 UBR7-Low下游细胞过程/途径及抑制物/蛋白靶点的确定 三阴性乳腺癌。我们的目标是1)表征UBR7的肿瘤抑制作用，并确定 UBR7缺失促进三阴性乳腺癌的遗传背景；2)确定UBR7缺失是否 通过改变染色质状态和钙粘附素基因促进EMT和乳腺癌转移；以及3) 确定UBR7缺陷的三重阴性乳腺癌的遗传和药物脆弱性。总的来说， 我们的研究将为理解表观基因组在三阴性乳腺中的作用提供重要的进展。 肿瘤进展和确定新的组蛋白修饰物参与的分子机制 癌症的发展。

ABSTRACT Triple negative breast cancer (TNBC) is the most aggressive breast cancer subtype with no targeted treatment available. Although we have made tremendous progress in regards to the genetic drivers of this disease, we have limited understanding of the epigenomic alterations that drive specific molecular subtypes of breast cancers. The epigenome consists of an array of chromatin modifications, which collectively form a dynamic chromatin state that impinges upon gene expression networks critical for maintaining cellular identity. Therefore, specific epigenomic alterations may act as drivers of different molecular phenotypes, however we have limited understanding of how specific chromatin patterns may be associated with specific molecular signatures such as basal-like breast cancer. Since epigenetic enzymes are targetable and epigenetic processes are reversible in nature, they could prove to be excellent targets for novel therapeutic strategies against specific molecular phenotypes. Our preliminary data suggests tumor suppressor activities for UBR7, a novel histone modifier, in triple negative breast cancer. We show that UBR7 acts as a E3 ubiquitin ligase for monoubiquitination of histone H2B at K120 residue and may transcriptionally regulate molecular signatures for invasive breast cancers. These data provide rationale for in depth characterization of tumor-suppressor function of UBR7 and identification of therapeutic vulnerabilities imparted by UBR7 loss. Our hypothesis is that UBR7 is a potent tumor suppressor in triple negative breast and promotes invasive behavior in triple- negative breast cancer partly by regulation of cadherin pathway. The objective of this proposal is to first perform in depth characterization of UBR7 tumor-suppressor activity using mouse models, elucidation of downstream cellular processes/pathways and identification of inhibitors/protein targets to inhibit in UBR7-low triple-negative breast cancers. We aim to 1) characterize tumor-suppressor role of UBR7 and determine the genetic context in which UBR7 loss promotes triple-negative breast cancers; 2) determine if UBR7 loss promotes EMT and breast cancer metastasis by alteration of chromatin states and Cadherin genes; and 3) determine genetic and pharmaceutical vulnerabilities of UBR7-deficient triple negative breast cancers. Overall, our studies will provide significant advances in understanding role of epigenome in triple-negative breast cancer tumor progression and define molecular mechanisms underlying contribution of new histone modifier to cancer development.