scholarly journals USP37 promotes deubiquitination of HIF2α in kidney cancer

2020 ◽  
Vol 117 (23) ◽  
pp. 13023-13032
Author(s):  
Kai Hong ◽  
Lianxin Hu ◽  
Xijuan Liu ◽  
Jeremy M. Simon ◽  
Travis S. Ptacek ◽  
...  
Keyword(s):  
Clear Cell ◽  
Hypoxia Inducible Factor ◽  
Three Dimensional ◽  
Xenograft Model ◽  
Dependent Manner ◽  
Potential Therapeutic Target ◽  
Cell Renal Cell Carcinoma ◽  
Von Hippel Lindau ◽  
Orthotopic Xenograft Model ◽  
Factor Α

Clear cell renal cell carcinoma (ccRCC) is characterized by loss of tumor suppressor Von Hippel Lindau (VHL) function, which leads to accumulation of hypoxia inducible factor α (including HIF1α and HIF2α). HIF2α was previously reported to be one of the major oncogenic drivers in ccRCC, however, its therapeutic targets remain challenging. Here we performed a deubiquitinase (DUB) complementary DNA (cDNA) library binding screen and discovered that ubiquitin-specific peptidase 37 (USP37) is a DUB that binds HIF2α and promotes HIF2α deubiquitination. As a result, USP37 promotes HIF2α protein stability in an enzymatically dependent manner, and depletion of USP37 leads to HIF2α down-regulation in ccRCC. Functionally, USP37 depletion causes decreased cell proliferation measured by MTS, two-dimensional (2D) colony formation as well as three-dimensional (3D) anchorage- independent growth. USP37 is also essential for maintaining kidney tumorigenesis in an orthotopic xenograft model and its depletion leads to both decreased primary kidney tumorigenesis and spontaneous lung metastasis. Our results suggest that USP37 is a potential therapeutic target in ccRCC.

scholarly journals Prognostic and Predictive Value of PBRM1 in Clear Cell Renal Cell Carcinoma

Cancers ◽  
2019 ◽  
Vol 12 (1) ◽  
pp. 16 ◽  
Author(s):  
Lucía Carril-Ajuria ◽  
María Santos ◽  
Juan María Roldán-Romero ◽  
Cristina Rodriguez-Antona ◽  
Guillermo de Velasco
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Clear Cell ◽  
Hypoxia Inducible Factor ◽  
Scoring Systems ◽  
Predictive Marker ◽  
Current Evidence ◽  
Cell Renal Cell Carcinoma ◽  
Von Hippel Lindau

Renal cell carcinoma (RCC) is the most frequent kidney solid tumor, the clear cell RCC (ccRCC) being the major histological subtype. The probability of recurrence and the clinical behavior of ccRCC will greatly depend on the different clinical and histopathological features, already incorporated to different scoring systems, and on the genomic landscape of the tumor. In this sense, ccRCC has for a long time been known to be associated to the biallelic inactivation of Von Hippel-Lindau (VHL) gene which causes aberrant hypoxia inducible factor (HIF) accumulation. Recently, next generation-sequencing technologies have provided the bases for an in-depth molecular characterization of ccRCC, identifying additional recurrently mutated genes, such as PBRM1 (≈40–50%), SETD2 (≈12%), or BAP1 (≈10%). PBRM1, the second most common mutated gene in ccRCC after VHL, is a component of the SWI/SNF chromatin remodeling complex. Different studies have investigated the biological consequences and the potential role of PBRM1 alterations in RCC prognosis and as a drug response modulator, although some results are contradictory. In the present article, we review the current evidence on PBRM1 as potential prognostic and predictive marker in both localized and metastatic RCC.

scholarly journals Rho-associated kinase 1 inhibition is synthetically lethal with von Hippel-Lindau deficiency in clear cell renal cell carcinoma

Oncogene ◽  
2016 ◽  
Vol 36 (8) ◽  
pp. 1080-1089 ◽  
Author(s):  
J M Thompson ◽  
Q H Nguyen ◽  
M Singh ◽  
M W Pavesic ◽  
I Nesterenko ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Clear Cell ◽  
Cell Renal Cell Carcinoma ◽  
Von Hippel Lindau ◽  
Synthetically Lethal

scholarly journals Emetine Promotes von Hippel-Lindau-Independent Degradation of Hypoxia-Inducible Factor-2α in Clear Cell Renal Carcinoma

2010 ◽  
Vol 78 (6) ◽  
pp. 1072-1078 ◽  
Author(s):  
Hye-Sik Kong ◽  
Sunmin Lee ◽  
Kristin Beebe ◽  
Bradley Scroggins ◽  
Gopal Gupta ◽  
...  
Keyword(s):  
Renal Carcinoma ◽  
Clear Cell ◽  
Hypoxia Inducible Factor ◽  
Clear Cell Renal Carcinoma ◽  
Von Hippel Lindau ◽  
Cell Renal Carcinoma

scholarly journals Functional succinate dehydrogenase deficiency is a common adverse feature of clear cell renal cancer

2021 ◽  
Vol 118 (39) ◽  
pp. e2106947118
Author(s):  
Ritesh K. Aggarwal ◽  
Rebecca A. Luchtel ◽  
Venkata Machha ◽  
Alexander Tischer ◽  
Yiyu Zou ◽  
...  
Keyword(s):  
Succinate Dehydrogenase ◽  
Catalytic Domain ◽  
Clear Cell ◽  
Competitive Inhibition ◽  
Hypoxia Inducible Factor ◽  
Tca Cycle ◽  
Product Inhibition ◽  
Down Regulation ◽  
Cell Renal Cell Carcinoma ◽  
Cancer Pathogenesis

Reduced succinate dehydrogenase (SDH) activity resulting in adverse succinate accumulation was previously considered relevant only in 0.05 to 0.5% of kidney cancers associated with germline SDH mutations. Here, we sought to examine a broader role for SDH loss in kidney cancer pathogenesis/progression. We report that underexpression of SDH subunits resulting in accumulation of oncogenic succinate is a common feature in clear cell renal cell carcinoma (ccRCC) (∼80% of all kidney cancers), with a marked adverse impact on survival in ccRCC patients (n = 516). We show that SDH down-regulation is a critical brake in the TCA cycle during ccRCC pathogenesis and progression. In exploring mechanisms of SDH down-regulation in ccRCC, we report that Von Hippel-Lindau loss-induced hypoxia-inducible factor–dependent up-regulation of miR-210 causes direct inhibition of the SDHD transcript. Moreover, shallow deletion of SDHB occurs in ∼20% of ccRCC. We then demonstrate that SDH loss-induced succinate accumulation contributes to adverse loss of 5-hydroxymethylcytosine, gain of 5-methylcytosine, and enhanced invasiveness in ccRCC via inhibition of ten-eleven translocation (TET)-2 activity. Intriguingly, binding affinity between the catalytic domain of recombinant TET-2 and succinate was found to be very low, suggesting that the mechanism of succinate-induced attenuation of TET-2 activity is likely via product inhibition rather than competitive inhibition. Finally, exogenous ascorbic acid, a TET-activating demethylating agent, led to reversal of the above oncogenic effects of succinate in ccRCC cells. Collectively, our study demonstrates that functional SDH deficiency is a common adverse feature of ccRCC and not just limited to the kidney cancers associated with germline SDH mutations.

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