The Role of WSB1 in Tumorigenesis

描述(申请人提供)：许多癌基因，如RAS，可诱导衰老表型，称为癌基因诱导衰老(OIS)。众所周知，OIS是肿瘤发生的屏障，必须抑制OIS才能使细胞被癌基因转化。然而，OIS在细胞转化过程中是如何被抑制的仍不清楚。除了抑制OIS外，癌基因还必须将细胞代谢重新编程为糖酵解，以促进肿瘤的发生和癌症的进展。RAS诱导代谢重编程的主要机制之一是上调低氧诱导因子1(HIF1)。目前也不清楚RAS是如何上调HIF1的。我们最近发现，E3泛素连接酶亚基WSB1在抑制OIS和促进RAS下游的代谢重编程中发挥作用。WSB1在包括乳腺癌、胰腺癌和黑色素瘤在内的几种人类癌症中过表达。我们发现WSB1被致癌的RAS和Myc上调，在表达致癌RAS的原代MEF中WSB1的表达有助于抑制OIS，导致异常增殖和细胞转化。相反，WSB1下调监管促进了OIS。从机制上讲，我们发现WSB1负向调节ATM，这对OIS的发生具有重要意义。此外，我们还发现WSB1上调HIF1？并促进与糖酵解增加一致的代谢表型。我们假设WSB1在早期致癌事件中起关键作用：1)通过ATM降解抑制DNA损伤反应和OIS；2)通过HIF1途径促进代谢重编程。为了验证这一假说，我们提出了以下具体目标：1.研究WSB1对ATM、DNA损伤反应和OIS的调控；2.研究HIF1？建立WSB1基因敲除小鼠，研究WSB1基因在肿瘤发生发展中的作用。这些研究将阐明RAS诱导肿瘤发生的新因素，以及抑制OIS和诱导代谢重编程的新机制。由于致癌RAS在多种人类癌症的发生发展中起重要作用，我们的研究将对目前对人类癌症的病因和进展的理解产生重大影响。

DESCRIPTION (provided by applicant): Many oncogenes such as Ras induce senescence-like phenotypes termed oncogene-induced senescence (OIS). It is well established that OIS is a barrier of tumorigenesis, and OIS has to be suppressed for cells to be transformed by oncogenes. However, how OIS is suppressed during cell transformation remains unclear. In addition to suppressing OIS, oncogenes have to reprogram cellular metabolism to glycolysis to facilitate tumorigenesis and cancer progression. One of the major mechanism by which Ras induce metabolic reprograming is through upregulation of hypoxia-inducible factor 1 (HIF1). It is also unclear how Ras upregulates HIF1. We recently found that the E3 ubiquitin ligase subunit WSB1 plays a role in suppressing OIS and promoting metabolic reprogramming downstream of Ras. WSB1 is overexpressed in several human cancers including breast cancer, pancreatic cancer and melanoma. We show that WSB1 is upregulated by oncogenic Ras and Myc, and expression of WSB1 in primary MEFs expressing oncogenic Ras contributes to the suppression of OIS, leading to abnormal proliferation and cell transformation. Conversely, WSB1 downregulation promotes OIS. Mechanistically, we found that WSB1 negatively regulates ATM, which is important for inducing OIS. In addition, we found that WSB1 upregulates HIF1? and promotes metabolic phenotypes consistent with increased glycolysis. We hypothesize that WSB1 is a key player in early oncogenic events to i) suppress the DNA damage response and OIS through ATM degradation and ii) promote metabolic reprogramming through the HIF1 pathway. To test this hypothesis, we propose the following specific aims: 1. Study the regulation of ATM, the DNA damage response and OIS by WSB1; 2. Study the regulation of HIF1? by WSB1; 3. Generate WSB1 knockout mice to study the role of WSB1 in cancer development and progression. These studies will elucidate both a new factor that contributes to Ras induced tumorigenesis and a novel mechanism by which OIS is suppressed and metabolic reprogramming is induced. Because oncogenic Ras plays an important role in tumorigenesis in a variety of human cancers, our study will have significant impact on current understanding of the cause and progression of human cancer.