HIF Pathways in Clear Cell Renal Cancer

Mapping Intimacies ◽

10.5772/intechopen.96539 ◽

2021 ◽

Author(s):

Olivia Lombardi ◽

David Robert Mole

Keyword(s):

Cell Proliferation ◽

Clear Cell ◽

Hypoxia Inducible Factor ◽

Von Hippel Lindau ◽

Pathway Activation ◽

Cellular Energetics ◽

Cellular Oxygen ◽

Immune Destruction ◽

Hif Pathway ◽

Cell Renal Cancer

Clear cell renal cancers (ccRCC) are characterized by inactivation of the VHL (von Hippel–Lindau) tumor suppressor. Work leading to the 2019 Nobel Prize for Physiology or Medicine has shown that this is central to cellular oxygen-sensing, orchestrated by the HIF (hypoxia-inducible factor) transcription factors. These regulate hundreds of genes that underpin many hallmarks of cancer, including angiogenesis, cellular energetics, cell proliferation, resisting cell death, and avoiding immune destruction. However, HIF also promotes processes that are detrimental to cancer cells. Therefore, the overall consequence of HIF pathway activation is a balance of these influences. We explore how variations in the HIF pathway during tumorigenesis alter this balance to promote ccRCC formation.

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MP35-19 SORBITOL AS A NOVEL MECHANISM OF HYPOXIA-INDUCIBLE FACTOR (HIF) PATHWAY ACTIVATION IN CLEAR CELL PAPILLARY RENAL CELL CARCINOMA (CCPRCC)

The Journal of Urology ◽

10.1016/j.juro.2014.02.1062 ◽

2014 ◽

Vol 191 (4S) ◽

Author(s):

A Ari Hakimi ◽

Satish K. Tickoo ◽

Jianing Xu ◽

Chung-Han Lee ◽

Roy Mano ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Renal Cell ◽

Clear Cell ◽

Hypoxia Inducible Factor ◽

Papillary Renal Cell Carcinoma ◽

Pathway Activation ◽

Hif Pathway

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

Molecular Pharmacology ◽

10.1124/mol.110.066514 ◽

2010 ◽

Vol 78 (6) ◽

pp. 1072-1078 ◽

Cited By ~ 11

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

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Hypoxia-Inducible Factor-Dependent Degeneration, Failure, and Malignant Transformation of the Heart in the Absence of the von Hippel-Lindau Protein

Molecular and Cellular Biology ◽

10.1128/mcb.01580-07 ◽

2008 ◽

Vol 28 (11) ◽

pp. 3790-3803 ◽

Cited By ~ 95

Author(s):

Li Lei ◽

Steve Mason ◽

Dinggang Liu ◽

Yan Huang ◽

Carolyn Marks ◽

...

Keyword(s):

Heart Failure ◽

Cardiac Myocyte ◽

Hypoxia Inducible Factor ◽

Premature Death ◽

Cardiac Tumors ◽

Human Heart Failure ◽

Von Hippel Lindau ◽

Chronic Activation ◽

Hif Pathway ◽

Transcription Factor 1

ABSTRACT Hypoxia-inducible transcription factor 1 (HIF-1) and HIF-2α regulate the expression of an expansive array of genes associated with cellular responses to hypoxia. Although HIF-regulated genes mediate crucial beneficial short-term biological adaptations, we hypothesized that chronic activation of the HIF pathway in cardiac muscle, as occurs in advanced ischemic heart disease, is detrimental. We generated mice with cardiac myocyte-specific deletion of the von Hippel-Lindau protein (VHL), an essential component of an E3 ubiquitin ligase responsible for suppressing HIF levels during normoxia. These mice were born at expected frequency and thrived until after 3 months postbirth, when they developed severe progressive heart failure and premature death. VHL-null hearts developed lipid accumulation, myofibril rarefaction, altered nuclear morphology, myocyte loss, and fibrosis, features seen for various forms of human heart failure. Further, nearly 50% of VHL−/− hearts developed malignant cardiac tumors with features of rhabdomyosarcoma and the capacity to metastasize. As compelling evidence for the mechanistic contribution of HIF-1α, the concomitant deletion of VHL and HIF-1α in the heart prevented this phenotype and restored normal longevity. These findings strongly suggest that chronic activation of the HIF pathway in ischemic hearts is maladaptive and contributes to cardiac degeneration and progression to heart failure.

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Cardiopulmonary function in two human disorders of the hypoxia‐inducible factor (HIF) pathway: von Hippel‐Lindau disease and HIF‐2α gain‐of‐function mutation

The FASEB Journal ◽

10.1096/fj.10-177378 ◽

2011 ◽

Vol 25 (6) ◽

pp. 2001-2011 ◽

Cited By ~ 53

Author(s):

Federico Formenti ◽

Philip A. Beer ◽

Quentin P. P. Croft ◽

Keith L. Dorrington ◽

Daniel P. Gale ◽

...

Keyword(s):

Hypoxia Inducible Factor ◽

Gain Of Function ◽

Cardiopulmonary Function ◽

Von Hippel Lindau ◽

Human Disorders ◽

Von Hippel Lindau Disease ◽

Hif Pathway

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Downregulation of integrins by von Hippel-Lindau (VHL) tumor suppressor protein is independent of VHL-directed hypoxia-inducible factor alpha degradation

Biochemistry and Cell Biology ◽

10.1139/o08-035 ◽

2008 ◽

Vol 86 (3) ◽

pp. 227-234 ◽

Cited By ~ 12

Author(s):

Qingzhou Ji ◽

Robert D. Burk

Keyword(s):

Tumor Suppressor ◽

Clear Cell ◽

Hypoxia Inducible Factor ◽

Intercellular Junctions ◽

Suppressor Gene ◽

Wild Type ◽

Von Hippel Lindau ◽

Degradation Activity ◽

Factor Alpha ◽

Vhl Tumor Suppressor Protein

Inactivation of the von Hippel-Lindau (VHL) tumor suppressor gene occurs in the majority of clear-cell renal cell carcinomas (RCCs). It was previously shown that VHL decreased the abundance of integrins α2, α5, and β1, which is consistent with VHL-associated changes in cell–cell and cell – extracellular matrix adhesions. We investigated the mechanism by which VHL downregulates integrins. Although VHL can target hypoxia-inducible factor alpha (HIFα) subunits for degradation, VHL-dependent reduction of integrins was independent of O2 concentration and HIFα levels. VHL reduced the half-lives of integrins, and this activity was blocked by proteasomal inhibition. Although ectopically expressed FLAG-VHL retained HIFα degradation activity, it neither downregulated integrins nor promoted adherens and tight intercellular junctions, in contrast to expressed wild-type VHL. Moreover, integrins co-immunoprecipitated with wild-type VHL, but not FLAG-VHL. These data indicate that the downregulation of integrins by VHL is distinct from the regulation of HIFα subunits by VHL, and suggests that the loss of this activity contributes to VHL-associated RCC development through disruption of adherens and tight junctions.

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363: Somatic Mutations of the Von Hippel-Lindau (VHL) Tumor Suppressor Gene, Expression of Hypoxia Inducible Factor-α and Vascula Endothelial Growth Factor in Chinese Sporadic Clear Cell Renal Cell Carcinomas and Their Relationships to Angiogenesis

The Journal of Urology ◽

10.1016/s0022-5347(18)34616-0 ◽

2005 ◽

Vol 173 (4S) ◽

pp. 99-99

Author(s):

Kan Gong ◽

Ning Zhang ◽

Yanqun Na

Keyword(s):

Gene Expression ◽

Growth Factor ◽

Somatic Mutations ◽

Clear Cell ◽

Hypoxia Inducible Factor ◽

Suppressor Gene ◽

Renal Cell Carcinomas ◽

Von Hippel Lindau ◽

Factor Α ◽

Endothelial Growth Factor

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USP37 promotes deubiquitination of HIF2α in kidney cancer

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.2002567117 ◽

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.

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