A Targetable GATA2-IGF2 Axis Confers Aggressiveness in Lethal Prostate Cancer

Vidal, Samuel J.; Rodríguez-Bravo, Verónica; Quinn, S. Aidan; Rodríguez-Barrueco, Ruth; Lujambio, Amaia; Williams, Estrelania; Sun, Xiaochen; Iglesia-Vicente, Janis de la; Lee, Albert; Readhead, Ben; Chen, Xintong; Galsky, Matthew D.; Esteve, Berta; Petrylak, Daniel P.; Dudley, Joel T.; Rabadán, Raúl; Silva, José M.; Hoshida, Yujin; Lowe, Scott W.; Cordon‐Cardo, Carlos; Domingo-Domènech, Josep

doi:10.1016/j.ccell.2014.11.013

Cited by 127 publications

(123 citation statements)

References 49 publications

(76 reference statements)

Supporting

Mentioning

120

Contrasting

Order By: Relevance

“…Chemoresistant cancer cell lines have been successfully used as models to efficiently identify key genes and signaling pathways associated with chemoresistance in human cancer (28)(29)(30). Establishment of chemoresistant cell lines from chemosensitive parental human ESCC cells in vitro mimics the in vivo process in which esophageal tumors acquire resistance to cytotoxic drugs after initial chemotherapy.…”

Section: Discussionmentioning

confidence: 99%

Competitive Binding Between Id1 and E2F1 to Cdc20 Regulates E2F1 Degradation and Thymidylate Synthase Expression to Promote Esophageal Cancer Chemoresistance

Guan

et al. 2016

Clinical Cancer Research

View full text Add to dashboard Cite

Purpose: Chemoresistance is a major obstacle in cancer therapy. We found that fluorouracil (5-FU)-resistant esophageal squamous cell carcinoma cell lines, established through exposure to increasing concentrations of 5-FU, showed upregulation of Id1, IGF2, and E2F1. We hypothesized that these genes may play an important role in cancer chemoresistance.Experimental Design: In vitro and in vivo functional assays were performed to study the effects of Id1-E2F1-IGF2 signaling in chemoresistance. Quantitative real-time PCR, Western blotting, immunoprecipitation, chromatin immunoprecipitation, and dual-luciferase reporter assays were used to investigate the molecular mechanisms by which Id1 regulates E2F1 and by which E2F1 regulates IGF2. Clinical specimens, tumor tissue microarray, and Gene Expression Omnibus datasets were used to analyze the correlations between gene expressions and the relationships between expression profiles and patient survival outcomes.Results: Id1 conferred 5-FU chemoresistance through E2F1-dependent induction of thymidylate synthase expression in esophageal cancer cells and tumor xenografts. Mechanistically, Id1 protects E2F1 protein from degradation and increases its expression by binding competitively to Cdc20, whereas E2F1 mediates Id1-induced upregulation of IGF2 by binding directly to the IGF2 promoter and activating its transcription. The expression level of E2F1 was positively correlated with that of Id1 and IGF2 in human cancers. More importantly, concurrent high expression of Id1 and IGF2 was associated with unfavorable patient survival in multiple cancer types.Conclusions: Our findings define an intricate E2F1-dependent mechanism by which Id1 increases thymidylate synthase and IGF2 expressions to promote cancer chemoresistance. The Id1-E2F1-IGF2 regulatory axis has important implications for cancer prognosis and treatment. Clin Cancer Res; 22(5); 1243-55. Ó2015 AACR.

show abstract

Section: Discussionmentioning

confidence: 99%

Competitive Binding Between Id1 and E2F1 to Cdc20 Regulates E2F1 Degradation and Thymidylate Synthase Expression to Promote Esophageal Cancer Chemoresistance

Guan

et al. 2016

Clinical Cancer Research

View full text Add to dashboard Cite

show abstract

“…It must be noted that there is concern about the potential utility of inhibiting FOXA1, given that it can seemingly act to both promote and suppress AR-mediated CRPC growth depending on context (see above). By contrast, a number of factors have converged to make the pioneer factor GATA2 an attractive target (He et al 2014): (i) GATA2 enhances both the expression and activity of AR; (ii) GATA2 is also required for signaling by AR-Vs; (iii) a small-molecule inhibitor of GATA2 (K7174) is available and (iv) GATA2 is reported to have an AR-independent role in driving chemoresistance in prostate cancer (Vidal et al 2015), meaning that its targeting could potentially suppress multiple oncogenic pathways. However, GATA2 plays a key role in multiple aspects of normal physiology, most notably hematopoiesis and angiogenesis, and GATA2 deficiency can result in susceptibility to infections, leukemia and other blood disorders (Hsu et al 2015); any future efforts to develop GATA2 inhibitors for CRPC will need to take this into account.…”

Section: Targeting Androgen Receptor Coregulatorsmentioning

confidence: 99%

Androgen receptor signaling in castration-resistant prostate cancer: a lesson in persistence

Coutinho¹,

Day²,

Tilley³

et al. 2016

Endocrine-Related Cancer

138

117

View full text Add to dashboard Cite

The androgen receptor (AR) signaling axis drives all stages of prostate cancer, including the lethal, drug-resistant form of the disease termed castration-resistant prostate cancer (CRPC), which arises after failure of androgen deprivation therapy (ADT). Persistent AR activity in spite of ADT and the second-generation AR-targeting agents enzalutamide and abiraterone is achieved in many cases by direct alterations to the AR signaling axis. Herein, we provide a detailed description of how such alterations contribute to the development and progression of CRPC. Aspects of this broad and ever-evolving field specifically addressed in this review include: the etiology and significance of increased AR expression; the frequency and role of gain-of-function mutations in the AR gene; the function of constitutively active, truncated forms of the AR termed AR variants and the clinical relevance of alterations to the activity and expression of AR coregulators. Additionally, we examine the novel therapeutic strategies to inhibit these classes of therapy resistance mechanisms, with an emphasis on emerging agents that act in a manner distinct from the current ligand-centric approaches. Throughout, we discuss how the central role of AR in prostate cancer and the constant evolution of the AR signaling axis during disease progression represent archetypes of two key concepts in oncology, oncogene addiction and therapy-mediated selection pressure.

show abstract

“…In this issue of Cancer Cell, Vidal et al (2015) have derived a docetaxel resistance gene expression signature from these models and identified 13 genes in this set that were also consistently deregulated in two advanced therapy-resistant PCa datasets. GATA2 was among these genes, and by IHC they confirmed that GATA2 was increased during progression from primary PCa to disseminated CRPC and found the highest levels in taxane-treated tumors.…”

mentioning

confidence: 98%

Taxane Resistance in Prostate Cancer Mediated by AR-Independent GATA2 Regulation of IGF2

2015

View full text Add to dashboard Cite

show abstract

A Targetable GATA2-IGF2 Axis Confers Aggressiveness in Lethal Prostate Cancer

Cited by 127 publications

References 49 publications

Competitive Binding Between Id1 and E2F1 to Cdc20 Regulates E2F1 Degradation and Thymidylate Synthase Expression to Promote Esophageal Cancer Chemoresistance

Competitive Binding Between Id1 and E2F1 to Cdc20 Regulates E2F1 Degradation and Thymidylate Synthase Expression to Promote Esophageal Cancer Chemoresistance

Androgen receptor signaling in castration-resistant prostate cancer: a lesson in persistence

Taxane Resistance in Prostate Cancer Mediated by AR-Independent GATA2 Regulation of IGF2

Contact Info

Product

Resources

About