The Role of WSB1 in Tumorigenesis

描述（由申请人提供）：许多癌基因（如Ras）诱导衰老样表型，称为癌基因诱导衰老（OIS）。众所周知，OIS是肿瘤发生的屏障，并且OIS必须被抑制以使细胞被癌基因转化。然而，在细胞转化过程中OIS如何被抑制仍不清楚。除了抑制OIS，癌基因还必须将细胞代谢重新编程为糖酵解，以促进肿瘤发生和癌症进展。Ras诱导代谢重编程的主要机制之一是通过上调缺氧诱导因子1（HIF 1）。目前还不清楚Ras如何上调HIF 1。 我们最近发现E3泛素连接酶亚基WSB 1在抑制OIS和促进Ras下游的代谢重编程中起作用。WSB 1在几种人类癌症中过表达，包括乳腺癌、胰腺癌和黑色素瘤。我们发现WSB 1被致癌Ras和Myc上调，并且在表达致癌Ras的原代MEFs中WSB 1的表达有助于抑制OIS，导致异常增殖和细胞转化。相反，WSB 1下调促进OIS。从机制上讲，我们发现WSB 1负调控ATM，这对诱导OIS很重要。此外，我们发现，WSB 1上调HIF 1？并促进与糖酵解增加一致的代谢表型。我们假设WSB 1是早期致癌事件的关键参与者，i）通过ATM降解抑制DNA损伤反应和OIS，ii）通过HIF 1途径促进代谢重编程。为了验证这一假设，我们提出了以下具体目标：1。研究WSB 1对ATM、DNA损伤反应和OIS的调控;研究HIF 1？WSB1; 3.产生WSB 1敲除小鼠以研究WSB 1在癌症发展和进展中的作用。这些研究将阐明一个新的因素，有助于Ras诱导的肿瘤发生和一个新的机制，OIS被抑制和代谢重编程诱导。由于致癌Ras在多种人类癌症的肿瘤发生中起着重要作用，我们的研究将对目前对人类癌症的原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.