Functional characterization of WAC, a candidate tumor suppressor gene in colorect

描述(申请人提供)：结直肠癌(CRC)是一种遗传性疾病，其进展是由癌基因和肿瘤抑制基因的突变或表观遗传改变的积累推动的。尽管取得了重大进展，但仍有更多的工作要做，以确定推动这一过程的异质遗传事件，并了解它们如何在疾病进展中协同作用。基于WW结构域与螺旋线圈(WAC)在小鼠肠道肿瘤三个正向遗传筛查中的功能丧失，我们已将其确定为结直肠癌的候选抑癌基因。尽管对WAC的功能知之甚少，但已有研究表明，WAC蛋白在多种生物过程中发挥着适配器的作用，包括转录偶联的组蛋白修饰和高尔基体的生物发生。基于初步数据显示，条件永生化的结肠上皮细胞中WAC的缺失导致体外锚定非依赖性生长增加，我们假设WAC的破坏与人类结直肠癌的发生有关。此外，在一组74例人类结直肠癌样本中对WAC基因进行测序发现，WAC基因非沉默突变的频率为2.7%。在未来的工作中，我们建议定义WAC表达减少有助于锚定独立性的机制，并表征癌症相关WAC突变体的功能缺陷和转化能力。最后，我们的目标是描述在锚定非依赖条件下由WAC复合体调控的完整转录程序，以描述一种新的肿瘤抑制途径，其破坏可能促进结直肠癌的进展。 公共卫生相关性：这项研究与公共健康的相关性结直肠癌是美国癌症相关死亡的第三大原因，也是一个重大的公共健康问题。这项拟议的工作将扩大我们对结直肠癌遗传机制的理解。这一理解将有助于开发更好的临床前模型，忠实地概括人类疾病。此外，发现和验证新的遗传驱动因素将为药物开发提供新的靶点，以改善结直肠癌的治疗选择和结果。

DESCRIPTION (provided by applicant): Colorectal Cancer (CRC) is a genetic disease in which progression is driven by the accumulation of mutations or epigenetic alterations in oncogenes and tumor suppressor genes. Despite significant progress, additional work remains to identify the heterogeneous genetic events that drive this process and to understand how they cooperate in disease progression. We have identified WW domain containing adaptor with coiled-coil (WAC) as a candidate tumor suppressor gene in colorectal cancer, based on its loss of function in three forward genetic screens for intestinal tumors in mice. Although little is know about the function of WAC, it has been shown that the WAC protein functions as an adaptor in multiple protein complexes in diverse biological processes, including transcription-coupled histone modification and golgi biogenesis. We hypothesize that disruption of WAC contributes to human colorectal cancer based on preliminary data showing that depletion of WAC in conditionally immortalized colonic epithelial cells leads to increased anchorage-independent growth in vitro. Additionally, sequencing the WAC gene in a set of 74 human colorectal cancer samples identified non- silent mutations in WAC at a frequency of 2.7%. In future work, we propose to define the mechanism by which decreased WAC expression contributes to anchorage-independence, and to characterize the functional deficits and transforming capacity of cancer-associated WAC mutants. Finally, we aim to describe the full transcriptional program regulated by the WAC complex under conditions of anchorage-independence, in order to describe a novel tumor suppressor pathway whose disruption may facilitate progression of colorectal cancer. PUBLIC HEALTH RELEVANCE: Relevance of this research to public health Colorectal cancer is the third-leading cause of cancer-related mortality in the United States and a significant publi health problem. The proposed work will expand our understanding of the genetic mechanisms of colorectal cancer. This understanding will contribute to the development of better pre-clinical models that faithfully recapitulate the human disease. Additionally, discovering and validating new genetic drivers will provide novel targets for drug development to improve treatment options and outcomes in colorectal cancer.