Mutant p53 cooperates with the SWI/SNF chromatin remodeling complex to regulate <i>VEGFR2</i> in breast cancer cells

Pfister, Neil T.; Fomin, Vitalay; Regunath, Kausik; Zhou, Jeffrey Y.; Zhou, Wen; Silwal-Pandit, Laxmi; Freed-Pastor, William A.; Laptenko, Oleg; Neo, Suat Peng; Bargonetti, Jill; Hoque, Mainul; Tian, Bin; Gunaratne, Jayantha; Engebraaten, Olav; Manley, James L.; Børresen-Dale, Anne Lise; Neilsen, Paul M.; Prives, Carol

doi:10.1101/gad.263202.115

Cited by 127 publications

(129 citation statements)

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“…Hence, TP53 mutations may lead to attenuation of immune responses, which can be recovered, at least in some models, with dendritic cell treatment together with antiangiogenesis agents. Expression analyses have demonstrated that VEGFR2 upregulation may be another mechanism by which mutant p53 controls angiogenesis (30). VEGFR2 is a receptor tyrosine kinase activated by binding of the VEGF-A ligand, and it is the main receptor mediating endothelial cell neovascularization.…”

Section: Discussionmentioning

confidence: 99%

“…Recently, TP53 mutational status was also shown to be predictive of response to the VEGFR inhibitor pazopanib in advanced sarcomas (45). The underlying mechanism of response may relate to TP53 mutations being associated with upregulation of VEGF-A and VEGFR2 expression (7,(30)(31)(32). Of interest in this regard, other tumor suppressors that are not directly druggable may also be actionable based on the upregulation of affected pathways when the suppressor gene is mutated (46).…”

Section: Discussionmentioning

confidence: 99%

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TP53Alterations Correlate with Response to VEGF/VEGFR Inhibitors: Implications for Targeted Therapeutics

Wheler

Janků

Naing

et al. 2016

Molecular Cancer Therapeutics

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

TP53Alterations Correlate with Response to VEGF/VEGFR Inhibitors: Implications for Targeted Therapeutics

Wheler

Janků

Naing

et al. 2016

Molecular Cancer Therapeutics

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“…Although effects of wtp53 are primarily mediated by sequence-specific DNA binding to cognate p53 response elements located in regulatory regions of p53 target genes, this DNA binding is commonly prevented by cancer-associated missense mutations clustered in the DNA binding domain. Nevertheless, mutp53 has a broad effect on gene expression profiles by binding genes indirectly through interactions with other transcription factors; for example p63/p73, Sp1/Sp3, NF-Y, ETS2, vitamin D receptor, or SREBP2 (4), and by regulating chromatin-modifying enzymes such as the ATP-dependent nucleosome remodeling complex SWI/SNF and the histone H3 lysine 4 methyltransferases MLL1 and MLL2 (14,16,17). By increasing the expression of various receptor tyrosine kinases (RTKs), such as transforming growth factor β (TGFβ) receptor, epidermal growth factor receptor (EGFR), hepatocyte growth factor receptor (HGFR/c-MET), and plateletderived growth factor (PDGF) receptor β, mutp53 enhances proinvasive signaling, which is further reinforced by stimulatory effects of mutp53 on integrin/RCP-driven receptor recycling (18)(19)(20)(21).…”

mentioning

confidence: 99%

Mutant p53 promotes tumor progression and metastasis by the endoplasmic reticulum UDPase ENTPD5

Vogiatzi

Brandt

Schneikert

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Mutations in the p53 tumor suppressor gene are the most frequent genetic alteration in cancer and are often associated with progression from benign to invasive stages with metastatic potential. Mutations inactivate tumor suppression by p53, and some endow the protein with novel gain of function (GOF) properties that actively promote tumor progression and metastasis. By comparative gene expression profiling of p53-mutated and p53-depleted cancer cells, we identified ectonucleoside triphosphate diphosphohydrolase 5 (ENTPD5) as a mutant p53 target gene, which functions as a uridine 5′-diphosphatase (UDPase) in the endoplasmic reticulum (ER) to promote the folding of N-glycosylated membrane proteins. A comprehensive pan-cancer analysis revealed a highly significant correlation between p53 GOF mutations and ENTPD5 expression. Mechanistically, mutp53 is recruited by Sp1 to the ENTPD5 core promoter to induce its expression. We show ENTPD5 to be a mediator of mutant p53 GOF activity in clonogenic growth, architectural tissue remodeling, migration, invasion, and lung colonization in an experimental metastasis mouse model. Our study reveals folding of N-glycosylated membrane proteins in the ER as a mechanism underlying the metastatic progression of tumors with mutp53 that could provide new possibilities for cancer treatment.M utations in the TP53 tumor suppressor gene are the most frequent genetic alterations in human cancer and commonly compromise the gene's tumor suppressor activity. p53-knockout mice succumb to tumors very early in life, arguing that the loss of function associated with p53 mutations is sufficient on its own to explain the high mutation frequency observed in patients with cancer (1). However, in striking contrast to mutations in other tumor suppressor genes, the vast majority of TP53 gene alterations in patients with cancer neither ablate p53 expression nor produce unstable or truncated proteins. Instead, p53 mutations are mostly missense mutations resulting in expression of mutant p53 (mutp53) proteins with only single-amino acid substitutions that accumulate to steady-state levels greatly exceeding those of wild-type p53 (wtp53) in normal tissues. Immunohistochemical positivity for p53 is therefore considered a diagnostic marker for the presence of a TP53 mutation (2). The high prevalence of missense mutations suggests a selective advantage during cancer progression, so it was hypothesized early on in p53 research that p53 mutations are neomorphic and endow the mutp53 protein with novel oncogenic functions that actively promote cancer progression and therapy resistance (2). These oncogenic properties are generally referred to as the mutp53 gain of function (GOF).Over the years, substantial experimental evidence for mutp53 GOF has accumulated (3-5). For example, mice expressing cancer-associated p53 hot spot mutations from the endogenous Trp53 gene locus are remarkably different from p53-deficient mice: tumorigenesis is accelerated, and the spectrum of tumors is shifted toward carcinomas and more meta...

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“…The TP53 mutation at codon 249 (R249S) could induce the transcription of MLL and the association with the switch/sucrose non-fermentable nucleosome remodeling complex [20]. In addition, R249S mutation could induce the transcription of SET domain bifurcated 1 (SETDB1), which is known as a histone H3 lysine 9 (H3K9) methyltransferase; SETDB1 could also suppress the degradation of the R249S mutation and play a role in hepatocarcinogenesis [21].…”

Section: Association Between Mutation Of Cancer-related Genes and Epimentioning

confidence: 99%

Clinical Significance of Epigenetic Alterations in Human Hepatocellular Carcinoma and Its Association with Genetic Mutations

Nishida

Kudo²

2016

Dig Dis

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Accumulation of genetic and epigenetic alterations is a hallmark of cancer genomes, including those in hepatocellular carcinoma (HCC). Particularly, in human HCC, epigenetic changes are more frequently observed than genetic changes in a variety of cancer-related genes, suggesting a potential role for epigenetic alterations during hepatocarcinogenesis. Several environmental factors, such as inflammation, obesity, and steatosis, are reported to affect the epigenetic status in hepatocytes, which could play a role in HCC development. In addition, genetic mutations in histone modulators and chromatin regulators would be critical for the acceleration of epigenetic alteration. It is also possible that major genetic mutations of HCC, such as TP53 and CNTTB1 mutations, are associated with the disturbance of epigenetic integrity. For example, specific TP53 mutations frequently induced by aflatoxin B1 exposure might affect histone modifiers and nucleosome remodelers. Generally, epigenetic alteration is reversible, because of which dysregulation of transcription takes place, without affecting protein structure. Therefore, differentiation therapy is one of the potential approaches for HCC with advanced epigenetic alterations. On the other hand, a tumor carrying an accumulation of genetic mutations would result in many abnormal proteins that could be recognized as non-self and could be targets for immune reactions; thus, immune-checkpoint blockers should be effective for HCCs with genetic hypermutation. Although the emergence of genetic and epigenetic alterations could be linked to each other and there could be some crossover or convergence between these cancer pathways, characterization of the mutation spectrum of genetic and epigenetic alterations could influence future HCC treatment.

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Mutant p53 cooperates with the SWI/SNF chromatin remodeling complex to regulate VEGFR2 in breast cancer cells

Cited by 127 publications

References 73 publications

TP53Alterations Correlate with Response to VEGF/VEGFR Inhibitors: Implications for Targeted Therapeutics

TP53Alterations Correlate with Response to VEGF/VEGFR Inhibitors: Implications for Targeted Therapeutics

Mutant p53 promotes tumor progression and metastasis by the endoplasmic reticulum UDPase ENTPD5

Clinical Significance of Epigenetic Alterations in Human Hepatocellular Carcinoma and Its Association with Genetic Mutations

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