SPOP Promotes Tumorigenesis by Acting as a Key Regulatory Hub in Kidney Cancer

Li, Guoqiang; Ci, Weimin; Karmakar, Subhradip; Chen, Ke; Dhar, Ruby; Fan, Zhixiang; Guo, Zhongqiang; Zhang, Jing; Ke, Youqi; Wang, Lu; Zhuang, Min; Hu, Shengdi; Li, Xuesong; Zhou, Liqun; Li, Xianghong; Calabrese, Matthew F.; Watson, Edmond R.; Prasad, Sandip M.; Rinker‐Schaeffer, Carrie W.; Eggener, Scott E.; Stricker, Thomas; Tian, Yong; Schulman, Brenda A.; Liu, Jiang; White, Kevin P.

doi:10.1016/j.ccr.2014.02.007

Cited by 153 publications

(212 citation statements)

References 64 publications

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“…We speculate that they may affect SPOP self‐association and have effects on both substrate turnover and cellular localization. In agreement with this proposal, cellular mislocalization of SPOP into the cytoplasm has been shown to drive tumorigenesis via targeting of an unnatural set of substrates (Li et al , 2014). …”

Section: Discussionmentioning

confidence: 63%

Higher‐order oligomerization promotes localization of SPOP to liquid nuclear speckles

et al. 2016

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Membrane‐less organelles in cells are large, dynamic protein/protein or protein/RNA assemblies that have been reported in some cases to have liquid droplet properties. However, the molecular interactions underlying the recruitment of components are not well understood. Herein, we study how the ability to form higher‐order assemblies influences the recruitment of the speckle‐type POZ protein (SPOP) to nuclear speckles. SPOP, a cullin‐3‐RING ubiquitin ligase (CRL3) substrate adaptor, self‐associates into higher‐order oligomers; that is, the number of monomers in an oligomer is broadly distributed and can be large. While wild‐type SPOP localizes to liquid nuclear speckles, self‐association‐deficient SPOP mutants have a diffuse distribution in the nucleus. SPOP oligomerizes through its BTB and BACK domains. We show that BTB‐mediated SPOP dimers form linear oligomers via BACK domain dimerization, and we determine the concentration‐dependent populations of the resulting oligomeric species. Higher‐order oligomerization of SPOP stimulates CRL3SPOP ubiquitination efficiency for its physiological substrate Gli3, suggesting that nuclear speckles are hotspots of ubiquitination. Dynamic, higher‐order protein self‐association may be a general mechanism to concentrate functional components in membrane‐less cellular bodies.

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Section: Discussionmentioning

confidence: 63%

Higher‐order oligomerization promotes localization of SPOP to liquid nuclear speckles

et al. 2016

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“…Although most of the identified functions of SPOP are related to tumor suppression, there is evidence that SPOP serves as a regulatory hub to promote clear cell renal cell carcinoma (ccRCC) tumorigenesis suggesting a possibility that tumor-related functions of SPOP might vary depending on tissue and cellular contexts (30). However, in this study, we have reasons to believe that SPOP could be a new therapeutic target for improving the treatment efficiency of glioma.…”

Section: Discussionmentioning

confidence: 91%

Decreased expression of the SPOP gene is associated with poor prognosis in glioma

Ding

Song

et al. 2014

International Journal of Oncology

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Abstract. This study suggests that speckle-type POZ protein (SPOP) may be a tumor suppressor gene and its prognostic value in human glioma. Real-time quantitative RT-PCR (qRT-PCR), western blotting, and immunohistochemical staining were used to examine SPOP expression in glioma tissues and normal brain (NB) tissues. The relationships between the SPOP expression levels, the clinicopathological factors, and patient survival were investigated. The molecular mechanisms of SPOP expression and its effects on cell viability, migration and invasion were also explored by MTT assay, wound-healing assays and Transwell assay. SPOP mRNA and protein levels were downregulated in glioma tissues compared to NB. Immunohistochemical staining results showed low expression in 62.2% (61/98) of glioma samples, while high expression in 75% (9/12) of NB samples, and the difference was statistically significant (P=0.014). In addition, decreased SPOP was associated disease progression in glioma samples, the expression level of SPOP was positively correlated with mean tumor diameter (MTD) (P= 0.021) and the status of tumor grade and histological type (WHO I, II, III and IV) (P= 0.032) in glioma patients. Additionally, the overall survival of patients with low SPOP expression was significantly worse than that of SPOP-high patients (P= 0.001). In vitro overexpression of SPOP markedly inhibited cell viability, migration and invasion in vitro. These findings suggest that SPOP has potential use as novel biomarker of glioma and may serve as an independent predictive factor for prognosis of glioma patients.

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“…Increased SPOP is associated with other forms of cancer, most notably ccRCC. The mechanism by which an increase in SPOP contributes to tumorigenesis is different from the mechanism by which SPOP inactivation leads to cancer (297). The gene encoding SPOP is stimulated by HIF-1a.…”

Section: Tumorigenesis: Somewhere Between Neutrality and Lethalitymentioning

confidence: 98%

“…Thus, hypoxia or mutations that inactivate ECV, the E3 ligase that targets HIF-1a (mutations in the receptor subunit VHL are common in ccRCC), increase the abundance of SPOP. By targeting several tumor suppressors, such as the phosphatase PTEN, ERK phosphatase, and transcription factors such as DAXX and GLI2, the increase in SPOP impairs apoptosis and promotes cell proliferation (297). Thus, E3 ligases with both oncogenic and tumor suppressor targets can promote cancer development when the abundance of the E3 ligase deviates from normal, independently from the direction of the deviation.…”

Section: Tumorigenesis: Somewhere Between Neutrality and Lethalitymentioning

confidence: 99%

Degrons in cancer

et al. 2017

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Degrons are the elements that are used by E3 ubiquitin ligases to target proteins for degradation. Most degrons are short linear motifs embedded within the sequences of modular proteins. As regulatory sites for protein abundance, they are important for many different cellular processes, such as progression through the cell cycle and monitoring cellular hypoxia. Degrons enable the elimination of proteins that are no longer required, preventing their possible dysfunction. Although the human genome encodes~600 E3 ubiquitin ligases, only a fraction of these enzymes have well-defined target degrons. Thus, for most cellular proteins, the destruction mechanisms are poorly understood. This is important for many diseases, especially for cancer, a disease that involves the enhanced expression of oncogenes and the persistence of encoded oncoproteins coupled with reduced abundance of tumor suppressors. Lossof-function mutations occur in the degrons of several oncoproteins, such as the transcription factors MYC and NRF2, and in various mitogenic receptors, such as NOTCH1 and several receptor tyrosine kinases. Mutations eliminating the function of the b-catenin degron are found in many cancers and are considered one of the most abundant mutations driving carcinogenesis. In this Review, we describe the current knowledge of degrons in cancer and suggest that increased research on the "dark degrome" (unknown degron-E3 relationships) would enhance progress in cancer research.

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SPOP Promotes Tumorigenesis by Acting as a Key Regulatory Hub in Kidney Cancer

Cited by 153 publications

References 64 publications

Higher‐order oligomerization promotes localization of SPOP to liquid nuclear speckles

Higher‐order oligomerization promotes localization of SPOP to liquid nuclear speckles

Decreased expression of the SPOP gene is associated with poor prognosis in glioma

Degrons in cancer

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