Modeling Renal Cell Carcinoma in Mice: <i>Bap1</i> and <i>Pbrm1</i> Inactivation Drive Tumor Grade

Gu, Yi; Cohn, Shannon M.; Christie, Alana; McKenzie, Tiffani; Wolff, Nicholas C.; Quyen, N.; Madhuranthakam, Ananth J.; Pedrosa, Iván; Wang, Tao; Dey, Anwesha; Busslinger, Meinrad; Xie, Xian Jin; Hammer, Robert E.; McKay, Renée M.; Kapur, Payal; Brugarolas, James

doi:10.1158/2159-8290.cd-17-0292

Cited by 141 publications

(150 citation statements)

References 65 publications

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“…Transcriptional profiling of human ccRCC indicate that PBRM1 mutant tumors have a hypoxic transcriptional signature (Sato et al, 2013), which is in agreement with recent reports that PBRM1 mutation amplifies the hypoxia inducible factor (HIF) transcriptional program signature induced upon von Hippel-Lindau (VHL) deletion in cell culture (Gao et al, 2017) and in a mouse model of renal cancer (Nargund et al, 2017). Recent work with kidney specific (KSP and PAX8) Cre mouse models indicate that VHL knockout or PBRM1 knockout alone is not sufficient for cancer formation but that both are required for kidney tumor formation in mice (Espana-Agusti et al, 2017;Gu et al, 2017;Nargund et al, 2017).…”

supporting

confidence: 86%

PBRM1 regulates the stress response in epithelial cells

Porter

Dhiman

Chowdhury

et al. 2018

Preprint

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Polybromo1 (PBRM1) is a chromatin remodeler subunit highly mutated in cancer, particularly renal clear cell carcinoma. PBRM1 is a member of the SWI/SNF subcomplex, PBAF (PBRM1-Brg1/Brm Associated Factors) and is characterized by six tandem bromodomains. Here we establish a role for PBRM1 in epithelial cell maintenance through the expression of genes involved in cell adhesion, metabolism, stress response, and apoptosis. In support of a general role for PBRM1 in stress response and apoptosis, we observe that loss of PBRM1 results in an increase in reactive oxygen species generation and a decrease in cellular viability under stress conditions. We find that loss of PBRM1 promotes cell growth under favorable conditions but is required for cell survival under conditions of cellular stress.

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supporting

confidence: 86%

PBRM1 regulates the stress response in epithelial cells

Porter

Dhiman

Chowdhury

et al. 2018

Preprint

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“…Pax8 -Cre was used to delete Vhl and Bap1 or Pbrm1 within the proximal and distal renal tubules, loops of Henle, collecting ducts, and parietal cells of the Bowman capsule [52]. Sglt2 - and Villin -Cre were also used for more specific deletion within proximal tubule epithelial cells.…”

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

120

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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.

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“…PBRM1deficient cancer cells exhibit a weakened HIF transcriptional signature (Gao et al, 2017). In mice, kidney-specific deletion of either Vhl or Pbrm1 does not lead to ccRCC, but their combined loss does (Gu et al, 2017;Nargund et al, 2017). Thus, PBRM1 restrains HIF's tumor-promoting activity.…”

Section: Introductionmentioning

confidence: 99%

High affinity binding of H3K14ac through collaboration of bromodomains 2, 4 and 5 is critical for the molecular and tumor suppressor functions of PBRM1

et al. 2019

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Polybromo‐1 ( PBRM 1) is an important tumor suppressor in kidney cancer. It contains six tandem bromodomains ( BD s), which are specialized structures that recognize acetyl‐lysine residues. While BD 2 has been found to bind acetylated histone H3 lysine 14 (H3K14ac), it is not known whether other BD s collaborate with BD 2 to generate strong binding to H3K14ac, and the importance of H3K14ac recognition for the molecular and tumor suppressor function of PBRM 1 is also unknown. We discovered that full‐length PBRM 1, but not its individual BD s, strongly binds H3K14ac. BD s 2, 4, and 5 were found to collaborate to facilitate strong binding to H3K14ac. Quantitative measurement of the interactions between purified BD proteins and H3K14ac or nonacetylated peptides confirmed the tight and specific association of the former. Interestingly, while the structural integrity of BD 4 was found to be required for H3K14ac recognition, the conserved acetyl‐lysine binding site of BD 4 was not. Furthermore, simultaneous point mutations in BD s 2, 4, and 5 prevented recognition of H3K14ac, altered promoter binding and gene expression, and caused PBRM 1 to relocalize to the cytoplasm. In contrast, tumor‐derived point mutations in BD 2 alone lowered PBRM 1's affinity to H3K14ac and also disrupted promoter binding and gene expression without altering cellular localization. Finally, overexpression of PBRM 1 variants containing point mutations in BD s 2, 4, and 5 or BD 2 alone failed to suppress tumor growth in a xenograft model. Taken together, our study demonstrates that BD s 2, 4, and 5 of PBRM 1 collaborate to generate high affinity to H3K14ac and tether PBRM 1 to chromatin. Mutations in BD 2 alone weaken these interactions, and this is sufficient to abolish its molecular and tumor suppressor functions.

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Modeling Renal Cell Carcinoma in Mice: Bap1 and Pbrm1 Inactivation Drive Tumor Grade

Cited by 141 publications

References 65 publications

PBRM1 regulates the stress response in epithelial cells

PBRM1 regulates the stress response in epithelial cells

Genetic and metabolic hallmarks of clear cell renal cell carcinoma

High affinity binding of H3K14ac through collaboration of bromodomains 2, 4 and 5 is critical for the molecular and tumor suppressor functions of PBRM1

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