SPOP Acts As The Key Regulatory Hub In Hypoxia-induced Kidney Tumorigenesis

Hypoxic stress and hypoxia-inducible factors (HIFs) play important roles in a wide range of tumors. Tumor cells can adapt to hypoxic microenvironment in several different ways to promote tumor growth. The clear cell Renal Cell Carcinoma (ccRCC), which is the most common type of kidney cancer with accounting for75%of all cases, is in a high hypoxia response state compared to the normal kidney samples and other subtypes of kidney cancer. Thus, kidney cancer is a good model to explore the adaption of cancer to hypoxia microenviroment. As hardly to be observed at early stage, about1/3RCC patients present with metastatic disease at the time of diagnosis. RCC is highly resistant to chemotherapy and radiotherapy, first-line treatment of metastatic disease relied on immunotherapies in the past two decades, despite low response rates and high rates of toxicity. Although recent targeted therapies that use inhibitors against VEGF, PDGF and mTOR signaling pathways have been developed, the majority of patients with advanced disease remain refractory to treatment, suggesting that critical targets remain unknow. Thus, it is urgent to determine the mechanism of tumorigenesis in kidney, which will benefit the discovery the new therapy targets. SPOP, which encodes an E3ubiquitin ligase substrates adapter, is a biomarker for ccRCC as it is overexpressed in nearly100%of primary and metastatic ccRCC. Thus, studies focus on the potential role of SPOP in promoting tumorigenesis in kidney cancer are crucial for the understanding to kidney cancer and the discovery of new drug targets for therapy. In this study, we aim to determine whether SPOP promotes tumorigenesis in kidney.Here we demeatrate that SPOP is a direct transcriptional target of HIFs in ccRCC. Furthermore, hypoxia results in cytoplasmic accumulation of SPOP which is sufficient to induce tumorigenesis. This tumorigenic activity occurs through the ubiquitination and degradation of multiple regulators of cellular proliferation and apoptosis, including the tumor suppressor PTEN, ERK phosphatases, the pro-apoptotic molecule Daxx and the Hedgehog pathway transcription factor Gli2. These targets are downregulated in all primary ccRCC examined, further support that SPOP orchestrates cancer phenotypes through the modulation of several critical cellular pathways. These results have elucidated a major mechanism that contributes to tumorigenesis in ccRCC, connecting hypoxia response and ubiquitin-mediated degradation of tumor suppressors. The oncogenic role of cytoplasmic SPOP makes it a promising candidate for therapeutic intervention.