Recently, Liu Jiang’s group at the Key Laboratory of Genomics and Information, Beijing Institute of Genomics, Chinese Academy of Sciences, in collaboration with researchers at the University of Chicago, has made a new development in the study of kidney cancer pathogenesis, revealing that overexpression and mislocalization of the nuclear protein SPOP (speckle-type POZ protein) is a central factor in the development of kidney cancer under physiological conditions of hypoxia. The related academic paper, SPOP Promotes Tumorigenesis by Acting as a Key Regulatory Hub in Kidney Cancer, was published online in Cancer Cell. Kidney cancer is one of the common malignancies in the genitourinary tract, accounting for about 3% of adult malignancies and 2% of cancer deaths. Currently, the main treatment for kidney cancer is radical nephrectomy; however, kidney cancer has an insidious onset and often lacks early clinical manifestations. About 30% of kidney cancer patients have metastasis at the time of diagnosis, and about 40% of patients with non-metastatic kidney cancer will recur after resection. Moreover, kidney cancer is not sensitive to radiotherapy and chemotherapy. Therefore, there is an urgent need to explore the molecular mechanism of kidney cancer development and find molecular targets for early diagnosis and treatment of kidney cancer. Renal clear cell carcinoma is the most common pathological type of kidney cancer, accounting for 75% of kidney cancers. SPOP is a bridge protein (adaptor) of ubiquitin ligase E3 family member Cul3 that binds to substrates and promotes their degradation by mediating the ubiquitination of many nuclear proteins, thus participating in the regulation of multiple cellular functions. Dr. Liu Jiang’s past study found that SPOP was overexpressed in 99% of renal clear cell carcinoma tumor tissues, while it was very low in the corresponding normal kidney tissues, and also found that SPOP was still overexpressed in metastatic renal clear cell carcinoma, clarifying that SPOP is a marker molecule for clear cell carcinoma (Science, 2009). Recent results from the group showed that the nuclear protein SPOP is overexpressed in kidney cancer tissues and mislocalized in the cytoplasm. In kidney cancer, the over-activated hypoxia-inducible factor HIF can transcriptionally regulate SPOP expression. The hypoxic microenvironment can drive the massive accumulation of overexpressed SPOP proteins in the cytoplasm of kidney cancer cells. Unlike the pro-apoptotic function of nuclear-localized SPOP, cytoplasmic SPOP could accelerate cell proliferation. Bioinformatic analysis and experimental validation revealed that cytoplasmic SPOP bound to the tumor suppressor PTEN and ERK phosphatase DUSP7 and degraded them through the ubiquitination pathway, thereby activating the PI3K-Akt and ERK signaling pathways. In addition, SPOP in kidney cancer also inhibits apoptosis and promotes cell proliferation by degrading Daxx and Gli2, which leads to tumorigenesis. In contrast, knockdown of SPOP specifically killed renal clear cell carcinoma, but had less effect on normal cells. The above results elucidate an important mechanism of SPOP in promoting kidney cancer formation, namely as a key hub protein linking hypoxic stress response and ubiquitination to degrade tumor suppressors. This study reveals the proto-oncogene function of SPOP in kidney cancer, providing clues for SPOP as a potential molecular probe or drug target, as well as a new theoretical basis for the diagnosis and treatment of kidney cancer. The study was funded by the National Natural Science Foundation of China, the Ministry of Science and Technology, and the Chinese Academy of Sciences.