A GATA4-regulated tumor suppressor network represses formation of malignant human astrocytomas

Agnihotri, Sameer; Wolf, Amparo; Muñoz, Diana Marcela; Smith, Christopher J.; Gajadhar, Aaron S.; Restrepo, Alberto; Clarke, Ian D.; Fuller, Gregory N.; Kesari, Santosh; Dirks, Peter B.; McGlade, C. Jane; Stanford, William; Aldape, Kenneth; Mischel, Paul S.; Hawkins, Cynthia; Guha, Abhijit

doi:10.1083/jcb1932oia3

Cited by 11 publications

(19 citation statements)

References 1 publication

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We identified a promoter methylation signature of 5 genes -ALDH1A2 lo , OSR2 lo , GATA4 hi , GRIA4 hi , and IRX4 hi -that not only characterized HPVdriven tumors, but also highly correlated with (and, hence, may serve as reliable predictor for) better OPSCC patient clinical outcome. Aberrant promoter hypermethylation of ALDH1A2, OSR2, GATA4, and GRIA4 as such is not a novel finding and has already been described in established human tumor cell lines or in tumor samples (27,(48)(49)(50)(51)(52)(53)(54)(55)(56). A striking novelty, however, was the robust correlation of the methylation signature score with the clinical outcome of OPSCC patients, which was confirmed in 3 independent cohorts, independent of HPV status or firstline treatment modality.…”

Section: Discussionmentioning

confidence: 81%

HPV-related methylation signature predicts survival in oropharyngeal squamous cell carcinomas

Kostareli¹,

Holzinger²,

Bogatyrova³

et al. 2013

J. Clin. Invest.

111

130

View full text Add to dashboard Cite

High-risk types of human papilloma virus (HPV) are increasingly associated with oropharyngeal squamous cell carcinoma (OPSCC). Strikingly, patients with HPV-positive OPSCC are highly curable with ionizing radiation and have better survival compared with HPV-negative patients, but the underlying molecular mechanisms remain poorly understood. We applied an array-based approach to monitor global changes in CpG island hypermethylation between HPV-negative and HPV-positive OPSCCs and identified a specific pattern of differentially methylated regions that critically depends on the presence of viral transcripts. HPV-related alterations were confirmed for the majority of candidate gene promoters by mass spectrometric, quantitative methylation analysis. There was a significant inverse correlation between promoter hypermethylation of ALDH1A2, OSR2, GATA4, GRIA4, and IRX4 and transcript levels. Interestingly, Kaplan-Meier analysis revealed that a combined promoter methylation pattern of low methylation levels in ALDH1A2 and OSR2 promoters and high methylation levels in GATA4, GRIA4, and IRX4 promoters was significantly correlated with improved survival in 3 independent patient cohorts. ALDH1A2 protein levels, determined by immunohistochemistry on tissue microarrays, confirmed the association with clinical outcome. In summary, our study highlights specific alterations in global gene promoter methylation in HPV-driven OPSCCs and identifies a signature that predicts the clinical outcome in OPSCCs.

show abstract

Section: Discussionmentioning

confidence: 81%

HPV-related methylation signature predicts survival in oropharyngeal squamous cell carcinomas

Kostareli¹,

Holzinger²,

Bogatyrova³

et al. 2013

J. Clin. Invest.

111

130

View full text Add to dashboard Cite

show abstract

“…Stereotactic guided intracranial injections in NOD-SCID mice were performed as previously described (17). Flank injections were performed by injecting 2 Â 10 6 million cells in 250 mL of PBS mixed with 250 mL of Matrigel (BD Biosciences, cat.…”

Section: In Vivo Mouse Model Experimentsmentioning

confidence: 99%

PINK1 Is a Negative Regulator of Growth and the Warburg Effect in Glioblastoma

et al. 2016

Self Cite

View full text Add to dashboard Cite

Proliferating cancer cells are characterized by high rates of glycolysis, lactate production, and altered mitochondrial metabolism. This metabolic reprogramming provides important metabolites for proliferation of tumor cells, including glioblastoma. These biological processes, however, generate oxidative stress that must be balanced through detoxification of reactive oxygen species (ROS). Using an unbiased retroviral loss-of-function screen in nontransformed human astrocytes, we demonstrate that mitochondrial PTEN-induced kinase 1 (PINK1) is a regulator of the Warburg effect and negative regulator of glioblastoma growth. We report that loss of PINK1 contributes to the Warburg effect through ROS-dependent stabilization of hypoxia-inducible factor-1A and reduced pyruvate kinase muscle isozyme 2 activity, both key regulators of aerobic glycolysis. Mechanistically, PINK1 suppresses ROS and tumor growth through FOXO3a, a master regulator of oxidative stress and superoxide dismutase 2. These findings highlight the importance of PINK1 and ROS balance in normal and tumor cells. PINK1 loss was observed in a significant number of human brain tumors including glioblastoma (n > 900) and correlated with poor patient survival. PINK1 overexpression attenuates in vivo glioblastoma growth in orthotopic mouse xenograft models and a transgenic glioblastoma model in Drosophila.

show abstract

“…We modeled gliomagenesis in vivo using GFAPHarvey Ras (HRas) V12 animals, 50% of which develop tumors that are histopathologically similar to human astrocytomas by age 12 wk, with a lifetime incidence of 95% (29). Although mutant V 12 Ha-Ras is not prevalent in human GBMs, this well-established model exhibits MAPK pathway activation at a level comparable with human GBMs (29)(30)(31)(32), suggesting that the levels of Ras pathway signaling in the GFAP-HRas V12 mouse model are not supraphysiological. To assess the contribution of a functional p53 pathway to the suppression of HRas V12 -induced gliomagenesis, hemizygous GFAP-HRas V12 mice were crossed into the p53 KI/KI [knock-in (KI)] background in which the endogenous p53 gene has been replaced by one encoding the p53ER TAM [estrogen receptor (ER)] fusion protein.…”

Section: Resultsmentioning

confidence: 99%

Using a preclinical mouse model of high-grade astrocytoma to optimize p53 restoration therapy

Shchors

Persson

Rostker

et al. 2013

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

View full text Add to dashboard Cite

Based on clinical presentation, glioblastoma (GBM) is stratified into primary and secondary types. The protein 53 (p53) pathway is functionally incapacitated in most GBMs by distinctive type-specific mechanisms. To model human gliomagenesis, we used a GFAPHRas V12 mouse model crossed into the p53ER TAM background, such that either one or both copies of endogenous p53 is replaced by a conditional p53ER TAM allele. The p53ER TAM protein can be toggled reversibly in vivo between wild-type and inactive conformations by administration or withdrawal of 4-hydroxytamoxifen (4-OHT), respectively. Surprisingly, gliomas that develop in GFAP-HRas V12 ; p53 +/KI mice abrogate the p53 pathway by mutating p19 ARF / MDM2 while retaining wild-type p53 allele. Consequently, such tumors are unaffected by restoration of their p53ER TAM allele. By contrast, gliomas arising in GFAP-HRas V12 ;p53 KI/KI mice develop in the absence of functional p53. Such tumors retain a functional p19 ARF /MDM2-signaling pathway, and restoration of p53ER TAM allele triggers p53-tumor-suppressor activity. Congruently, growth inhibition upon normalization of mutant p53 by a small molecule, Prima-1, in human GBM cultures also requires p14 ARF /MDM2 functionality. Notably, the antitumoral efficacy of p53 restoration in tumor-bearing GFAP-HRas V12 ;p53 KI/KI animals depends on the duration and frequency of p53 restoration. Thus, intermittent exposure to p53ER TAM activity mitigated the selective pressure to inactivate the p19 ARF /MDM2/p53 pathway as a means of resistance, extending progression-free survival. Our results suggest that intermittent dosing regimes of drugs that restore wild-type tumorsuppressor function onto mutant, inactive p53 proteins will prove to be more efficacious than traditional chronic dosing by similarly reducing adaptive resistance.preclinical model | Nutlin 3 | intermittent treatment

show abstract

A GATA4-regulated tumor suppressor network represses formation of malignant human astrocytomas

Cited by 11 publications

References 1 publication

HPV-related methylation signature predicts survival in oropharyngeal squamous cell carcinomas

HPV-related methylation signature predicts survival in oropharyngeal squamous cell carcinomas

PINK1 Is a Negative Regulator of Growth and the Warburg Effect in Glioblastoma

Using a preclinical mouse model of high-grade astrocytoma to optimize p53 restoration therapy

Contact Info

Product

Resources

About