MYC activation cooperates with Vhl and Ink4a/Arf loss to induce clear cell renal cell carcinoma

Bailey, Sean T.; Smith, Aleisha M.; Kardos, Jordan; Wobker, Sara E.; Wilson, Harper L.; Krishnan, Bhavani; Saito, Ryoichi; Lee, Hyo Jin; Zhang, Jing; Eaton, Samuel C.; Williams, Lindsay A.; Manocha, Ujjawal; Peters, Dorien J.M.; Pan, Xiaowei; Carroll, Thomas J.; Felsher, Dean W.; Walter, Vonn; Zhang, Qing; Parker, Joel S.; Yeh, Jen Jen; Moffitt, Richard A.; Leung, Janny; Kim, William Y.

doi:10.1038/ncomms15770

Cited by 71 publications

(67 citation statements)

References 62 publications

(82 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In another report, the combination of MYC overexpression along with further deletion of Vhl and/or Cdkn2a (encoding Ink4/Arf) was investigated for the ability to induce papillary or clear cell renal cell carcinoma [62]. This study utilized the Ksp promoter to drive expression of a doxycycline-inducible Myc transgene.…”

Section: Genetic Mouse Models Of Renal Cell Carcinomamentioning

confidence: 99%

Genetic and metabolic hallmarks of clear cell renal cell carcinoma

Sanchez

Simon

2018

Biochimica et Biophysica Acta (BBA) - Reviews on Cancer

117

View full text Add to dashboard Cite

Clear cell renal cell carcinoma (ccRCC) is a malignancy characterized by deregulated hypoxia-inducible factor signaling, mutation of several key chromatin modifying enzymes, and numerous alterations in cellular metabolism. Pre-clinical studies have historically been limited to cell culture models, however, the identification of critical tumor suppressors and oncogenes from large-scale patient sequencing data has led to several new genetically engineered mouse models with phenotypes reminiscent of ccRCC. In this review, we summarize recent literature on these topics and discuss how they inform targeted therapeutic approaches for the treatment of ccRCC.

show abstract

Section: Genetic Mouse Models Of Renal Cell Carcinomamentioning

confidence: 99%

Genetic and metabolic hallmarks of clear cell renal cell carcinoma

Sanchez

Simon

2018

Biochimica et Biophysica Acta (BBA) - Reviews on Cancer

117

View full text Add to dashboard Cite

show abstract

“…Accordingly, several groups have recently demonstrated the development of ccRCC in mice models upon the combined loss of Vhl and different genes; Harlander et al [20] showed that combined deletion of Vhl, p53 and Rb1 specifically in renal epithelial cells in mice caused ccRCC arising from proximal tubule epithelial cells. Nargund et al [21] demonstrated that activation of mTORC1 constituted a third driver event after loss of Vhl and Pbmr1 in their ccRCC tumour model, and Bailey et al [22] showed that Myc activation when combined with Vhl and Cdkn2a (Ink4a/Arf) deletion, produced murine kidney tumours that approximate human ccRCC. pVHL might also exert a broader role in maintaining renal integrity.…”

Section: Introductionmentioning

confidence: 99%

The <b><i>von Hippel-Lindau</i></b> Gene Is Required to Maintain Renal Proximal Tubule and Glomerulus Integrity in Zebrafish Larvae

Rooijen

Hoek

Logister

et al. 2018

Nephron

View full text Add to dashboard Cite

Background: von Hippel-Lindau (VHL) disease is characterized by the development of benign and malignant tumours in many organ systems, including renal cysts and clear cell renal cell carcinoma. It is not completely understood what underlies the development of renal pathology, and the use of murine Vhl models has been challenging due to limitations in disease conservation. We previously described a zebrafish model bearing inactivating mutations in the orthologue of the human VHL gene. Methods: We used histopathological and functional assays to investigate the pronephric and glomerular developmental defects in vhl mutant zebrafish, supported by human cell culture assays. Results: Here, we report that vhl is required to maintain pronephric tubule and glomerulus integrity in zebrafish embryos. vhl mutant glomeruli are enlarged, cxcr4a+ capillary loops are dilated and the Bowman space is widened. While we did not observe pronephric cysts, the cells of the proximal convoluted and anterior proximal straight tubule are enlarged, periodic acid schiff (PAS) and Oil Red O positive, and display a clear cytoplasm after hematoxylin and eosine staining. Ultrastructural analysis showed the vhl^–/– tubule to accumulate large numbers of vesicles of variable size and electron density. Microinjection of the endocytic fluorescent marker AM1–43 in zebrafish embryos revealed an accumulation of endocytic vesicles in the vhl mutant pronephric tubule, which we can recapitulate in human cells lacking VHL. Conclusions: Our data indicates that vhl is required to maintain pronephric tubule and glomerulus integrity during zebrafish development, and suggests a role for VHL in endocytic vesicle trafficking.

show abstract

“…( Myc ), Vhl loss drives spontaneous ccRCC formation in mouse models (7)(8)(9)(10)(11). VHL encodes an E3 ubiquitin ligase ( 12,13 ) that targets HIF1α ( HIF1A ) and HIF2α ( EPAS1 ) for degradation ( 14,15 ).…”

mentioning

confidence: 99%

VHL Deficiency Drives Enhancer Activation of Oncogenes in Clear Cell Renal Cell Carcinoma

et al. 2017

View full text Add to dashboard Cite

Protein-coding mutations in clear cell renal cell carcinoma (ccRCC) have been extensively characterized, frequently involving inactivation of the von Hippel-Lindau ( VHL ) tumor suppressor. Roles for noncoding cis -regulatory aberrations in ccRCC tumorigenesis, however, remain unclear. Analyzing 10 primary tumor/normal pairs and 9 cell lines across 79 chromatin profi les, we observed pervasive enhancer malfunction in ccRCC, with cognate enhancer-target genes associated with tissue-specifi c aspects of malignancy. Superenhancer profi ling identifi ed ZNF395 as a ccRCCspecifi c and VHL-regulated master regulator whose depletion causes near-complete tumor elimination in vitro and in vivo . VHL loss predominantly drives enhancer/superenhancer deregulation more so than promoters, with acquisition of active enhancer marks (H3K27ac, H3K4me1) near ccRCC hallmark genes. Mechanistically, VHL loss stabilizes HIF2α-HIF1β heterodimer binding at enhancers, subsequently recruiting histone acetyltransferase p300 without overtly affecting preexisting promoter-enhancer interactions. Subtype-specifi c driver mutations such as VHL may thus propagate unique pathogenic dependencies in ccRCC by modulating epigenomic landscapes and cancer gene expression. SIGnIFICAnCE:Comprehensive epigenomic profi ling of ccRCC establishes a compendium of somatically altered cis -regulatory elements, uncovering new potential targets including ZNF395, a ccRCC master regulator. Loss of VHL , a ccRCC signature event, causes pervasive enhancer malfunction, with binding of enhancer-centric HIF2α and recruitment of histone acetyltransferase p300 at preexisting lineage-specifi c promoter-enhancer complexes. Cancer Discov; 7(11); 1284-305.

show abstract

MYC activation cooperates with Vhl and Ink4a/Arf loss to induce clear cell renal cell carcinoma

Cited by 71 publications

References 62 publications

Genetic and metabolic hallmarks of clear cell renal cell carcinoma

Genetic and metabolic hallmarks of clear cell renal cell carcinoma

The <b><i>von Hippel-Lindau</i></b> Gene Is Required to Maintain Renal Proximal Tubule and Glomerulus Integrity in Zebrafish Larvae

VHL Deficiency Drives Enhancer Activation of Oncogenes in Clear Cell Renal Cell Carcinoma

Contact Info

Product

Resources

About