The Tumor Suppressive Role of CHD5

描述（由申请人提供）：本提案的总体目标是深入了解癌症发生的过程，以便设计更有效的抗癌治疗方法。作为第一步，必须确定控制癌症的基因。其次，确定这些基因的产物在正常情况下是如何起作用的，以及这些产物在肿瘤发生过程中是如何改变的，将是很重要的。最近的进展已经确定CHD5是一个定位于人类1p36的肿瘤抑制基因，这个基因组区域30年来一直被怀疑含有这样一个预防癌症的基因。具有代表1p36区域的增益和损失的模型是确定肿瘤抑制子所在位置的关键。进一步的研究确定了CHD5是该区域的肿瘤抑制因子，并揭示了它作为癌症保护蛋白网络的主开关。事实上，CHD5在神经胶质瘤（一种人类脑癌）中经常被删除。CHD5是一种具有预测染色质重塑能力的蛋白质，这表明它具有超越DNA本身水平调节我们基因组的能力，这可能暗示CHD5缺乏是多种人类恶性肿瘤的罪魁祸首。本提案的重点是确定受损CHD5在人类癌症中的影响，并阐明CHD5的肿瘤抑制机制。这将通过：1)生成CHD5活性改变的小鼠模型并监测这些模型中的癌症。这些模型还将用于研究在人类癌症中发现的CHD5或其相关肿瘤抑制网络中的错误如何阻碍其肿瘤保护能力；2)识别有缺陷CHD5的人类癌症；3)阐明CHD5预防癌症的机制基础，确定CHD5无法调节肿瘤抑制网络如何引发肿瘤发生。最终，弄清楚CHD5如何正常工作，并确定导致其缺陷的事件，将有助于更好地治疗各种人类恶性肿瘤。相关性：在许多人类癌症中发现了包含CHD5的基因组区域的缺失，包括那些影响大脑和血液的癌症，以及那些发生在乳腺癌、结肠癌和前列腺癌等常见癌症中的癌症。既然CHD5已被证明是该区域的肿瘤抑制因子，它的缺失或失活可能是导致许多这些癌症的原因。因此，有必要进一步研究CHD5在癌症中的作用，以确定CHD5是否为设计更有效的抗癌疗法提供了新的策略。

DESCRIPTION (provided by applicant): The overall goal of this proposal is to gain insight into the process of carcinogenesis so that more effective anti- cancer therapies can be designed. As a first step, genes that regulate cancer must be identified. Secondly, it will be important to determine how the products of these genes normally function, and how these products are altered during tumorigenesis. Recent progress has identified CHD5 as a tumor suppressor gene mapping to human 1p36, a region of the genome that has been suspected to harbor such a cancer-preventing gene for three decades. Models with gain and loss of regions representing 1p36 were key in determining where the tumor suppressor resided. Further work identified CHD5 as the tumor suppressor in the region, and revealed that it acts as a master switch for a network of cancer-protective proteins. Indeed, CHD5 is frequently deleted in glioma, a type of brain cancer in humans. CHD5 is a protein with predicted chromatin-remodeling capabilities, suggesting that it has the power to regulate our genomes above and beyond the level of the DNA itself, potentially implicating CHD5 deficiency as the culprit in a variety of human malignancies. This proposal is focused on determining the impact of compromised CHD5 in human cancer and elucidating CHD5's mechanism of tumor suppression. This will be done by: 1) generating mouse models with altered CHD5 activity and monitoring cancer in these models. These models will also be used to investigate how errors in CHD5 or its associated tumor suppressive network which are found in human cancers thwart its tumor protective capabilities; 2) identifying human cancers that have defective CHD5; 3) elucidating the mechanistic basis of CHD5's ability to prevent cancer and determining how the inability of CHD5 to regulate the tumor suppressive network initiates tumorigenesis. Ultimately, figuring out how CHD5 normally works and defining the events that render it defective will lead to better treatments for a variety of human malignancies. Relevance: Deletion of the region of the genome encompassing CHD5 has been found in many human cancers including those affecting the brain and blood, as well as those occurring in common cancers such breast, colon, and prostate. Now that CHD5 has been shown to be a tumor suppressor in this region, its loss or inactivation could be responsible for many of these cancers. Therefore, a further study of the role of CHD5 in cancer is warranted to determine whether CHD5 offers novel strategies for designing more powerful anti-cancer therapies.