DAB2IP

Gene Summary

Gene:DAB2IP; DAB2 interacting protein
Aliases: AIP1, AIP-1, AF9Q34, DIP1/2
Location:9q33.2
Summary:DAB2IP is a Ras (MIM 190020) GTPase-activating protein (GAP) that acts as a tumor suppressor. The DAB2IP gene is inactivated by methylation in prostate and breast cancers (Yano et al., 2005 [PubMed 15386433]).[supplied by OMIM, May 2010]
Databases:VEGA, OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:disabled homolog 2-interacting protein
Source:NCBIAccessed: 15 March, 2017

Ontology:

What does this gene/protein do?
Show (38)

Cancer Overview

Research Indicators

Publications Per Year (1992-2017)
Graph generated 15 March 2017 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • Cell Proliferation
  • Genetic Predisposition
  • Bladder Cancer
  • Tumor Suppressor Proteins
  • Single Nucleotide Polymorphism
  • DNA Methylation
  • p53 Protein
  • Immunohistochemistry
  • Neoplasm Invasiveness
  • ras Proteins
  • Cancer Gene Expression Regulation
  • Molecular Sequence Data
  • Breast Cancer
  • Risk Factors
  • Drug Resistance
  • Western Blotting
  • Signal Transduction
  • Young Adult
  • Amino Acid Sequence
  • Biomarkers, Tumor
  • ras GTPase-Activating Proteins
  • Base Sequence
  • Vimentin
  • Chromosome 9
  • RTPCR
  • Down-Regulation
  • Tumor Suppressor Gene
  • Lung Cancer
  • Genotype
  • Gene Expression
  • Promoter Regions
  • Watchful Waiting (Prostate Ca)
  • DNA Sequence Analysis
  • Protein Tyrosine Phosphatase, Non-Receptor Type 6
  • Apoptosis
  • Enhancer of Zeste Homolog 2 Protein
  • TNF
  • Polycomb Repressive Complex 2
  • Messenger RNA
  • Transfection
  • Prostate Cancer
Tag cloud generated 15 March, 2017 using data from PubMed, MeSH and CancerIndex

Specific Cancers (4)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: DAB2IP (cancer-related)

Liu L, Xu C, Hsieh JT, et al.
DAB2IP in cancer.
Oncotarget. 2016; 7(4):3766-76 [PubMed] Free Access to Full Article Related Publications
DOC-2/DAB2 is a member of the disable gene family that features tumor-inhibiting activity. The DOC-2/DAB2 interactive protein, DAB2IP, is a new member of the Ras GTPase-activating protein family. It interacts directly with DAB2 and has distinct cellular functions such as modulating different signal cascades associated with cell proliferation, survival, apoptosis and metastasis. Recently, DAB2IP has been found significantly down regulated in multiple types of cancer. The aberrant alteration of DAB2IP in cancer is caused by a variety of mechanisms, including the aberrant promoter methylation, histone deacetylation, and others. Reduced expression of DAB2IP in neoplasm may indicate a poor prognosis of many malignant cancers. Moreover, DAB2IP stands for a promising direction for developing targeted therapies due to its capacity to inhibit tumor cell growth in vitro and in vivo. Here, we summarize the present understanding of the tumor suppressive role of DAB2IP in cancer progression; the mechanisms underlying the dysregulation of DAB2IP; the gene functional mechanism and the prospects of DAB2IP in the future cancer research.

Yeh CR, Ou ZY, Xiao GQ, et al.
Infiltrating T cells promote renal cell carcinoma (RCC) progression via altering the estrogen receptor β-DAB2IP signals.
Oncotarget. 2015; 6(42):44346-59 [PubMed] Free Access to Full Article Related Publications
Previous studies indicated the T cells, one of the most common types of immune cells existing in the microenvironment of renal cell carcinoma (RCC), may influence the progression of RCC. The potential linkage of T cells and the estrogen receptor beta (ERβ), a key player to impact RCC progression, however, remains unclear. Our results demonstrate that RCC cells can recruit more T cells than non-malignant kidney cells. Using an in vitro matrigel invasion system, we found infiltrating T cells could promote RCC cells invasion via increasing ERβ expression and transcriptional activity. Mechanism dissection suggested that co-culturing T cells with RCC cells released more T cell attraction factors, including IFN-γ, CCL3 and CCL5, suggesting a positive regulatory feed-back mechanism. Meanwhile, infiltrating T cells may also promote RCC cell invasion via increased ERβ and decreased DAB2IP expressions, and knocking down DAB2IP can then reverse the T cells-promoted RCC cell invasion. Together, our results suggest that infiltrating T cells may promote RCC cell invasion via increasing the RCC cell ERβ expression to inhibit the tumor suppressor DAB2IP signals. Further mechanism dissection showed that co-culturing T cells with RCC cells could produce more IGF-1 and FGF-7, which may enhance the ERβ transcriptional activity. The newly identified relationship between infiltrating T cells/ERβ/DAB2IP signals may provide a novel therapeutic target in the development of agents against RCC.

Min J, Liu L, Li X, et al.
Absence of DAB2IP promotes cancer stem cell like signatures and indicates poor survival outcome in colorectal cancer.
Sci Rep. 2015; 5:16578 [PubMed] Free Access to Full Article Related Publications
Metastasis is a critical factor for the high mortality of colorectal cancer (CRC), but its mechanism is not completely understood. Epithelial-mesenchymal transition (EMT) is thought to play a key role in metastasis and also increases the cancer stem cell (CSC) feature that facilitates metastatic colonization. In this study, we investigated the biological roles of DAB2IP regulating EMT and stem cell-like features in human CRC. We demonstrate that DAB2IP suppresses NF-κB-mediated EMT and CSC features in CRC cells. In DAB2IP knockout mice, we discovered the hyperplasia in colonic epithelium which aberrantly represents the mesenchymal feature and NF-κB pathway activation. In clinic CRC tissue, we also reveal that reduced DAB2IP can enrich the CD133(+) subpopulation. DAB2IP expression was inversely correlated with tumor differentiation and metastasis, and patients with lower DAB2IP expression had shorter overall survival time. Taken together, our study demonstrates that DAB2IP inhibits NF-κB-inducing EMT and CSC to suppress the CRC progression, and also suggests that DAB2IP is a beneficial prediction factor for CRC patient prognosis.

Zhou J, Ning Z, Wang B, et al.
DAB2IP loss confers the resistance of prostate cancer to androgen deprivation therapy through activating STAT3 and inhibiting apoptosis.
Cell Death Dis. 2015; 6:e1955 [PubMed] Related Publications
Loss of DAB2IP, a novel tumor suppressor gene, is associated with the high risk of aggressive prostate cancer (PCa). Previously, we reported that DAB2IP modulated androgen receptor activation in the development of castration-resistant PCa; however, its direct action on the failure of androgen deprivation therapy (ADT) remains largely unknown. In this study, we showed that DAB2IP knockdown could significantly enhance in vitro growth and colony formation of PCa cells following ADT as well as tumorigenicity in pre-castrated nude mice. In addition, DAB2IP loss stabilized mitochondrial transmembrane potential, prevented release of cytochrome c, Omi/HtrA2 and Smac from the mitochondria to the cytoplasm and inhibited intrinsic apoptosis induced by ADT. Mechanistically, DAB2IP could interact with the signal transducer and activator of transcription 3 (STAT3) via its unique PR domain and suppress STAT3 phosphorylation and transactivation, leading to the inhibition of survivin expression in PCa cells. Moreover, the luminal epithelia in DAB2IP(-/-) mice with more activated STAT3 and survivin expression were resistant to castration-induced apoptosis. Consistently, DAB2IP expression inversely correlated with STAT3 phosphorylation and survivin expression in PCa patients. Together, our data indicate that DAB2IP loss reprograms intracellular signal transduction and anti-apoptotic gene expression, which potentiates PCa cell survival from ADT-induced cell death.

Yun EJ, Zhou J, Lin CJ, et al.
Targeting Cancer Stem Cells in Castration-Resistant Prostate Cancer.
Clin Cancer Res. 2016; 22(3):670-9 [PubMed] Free Access to Full Article Related Publications
PURPOSE: Clinical evidence suggests increased cancer stem cells (CSCs) in a tumor mass may contribute to the failure of conventional therapies because CSCs seem to be more resistant than differentiated tumor cells. Thus, unveiling the mechanism regulating CSCs and candidate target molecules will provide new strategy to cure the patients.
EXPERIMENTAL DESIGN: The stem-like cell properties were determined by a prostasphere assay and dye exclusion assay. To find critical stem cell marker and reveal regulation mechanism, basic biochemical and molecular biologic methods, such as quantitative real-time PCR, Western blot, reporter gene assay, and chromatin immunoprecipitation assay, were used. In addition, to determine the effect of combination therapy targeting both CSCs and its progeny, in vitro MTT assay and in vivo xenograft model was used.
RESULTS: We demonstrate immortalized normal human prostate epithelial cells, appeared nontumorigenic in vivo, become tumorigenic, and acquire stem cell phenotype after knocking down a tumor suppressor gene. Also, those stem-like cells increase chemoresistance to conventional anticancer reagent. Mechanistically, we unveil that Wnt signaling is a key pathway regulating well-known stem cell marker CD44 by directly interacting to the promoter. Thus, by targeting CSCs using Wnt inhibitors synergistically enhances the efficacy of conventional drugs. Furthermore, the in vivo mouse model bearing xenografts showed a robust inhibition of tumor growth after combination therapy.
CONCLUSIONS: Overall, this study provides strong evidence of CSC in castration-resistant prostate cancer. This new combination therapy strategy targeting CSC could significantly enhance therapeutic efficacy of current chemotherapy regimen only targeting non-CSC cells.

Wu K, Wang B, Chen Y, et al.
DAB2IP regulates the chemoresistance to pirarubicin and tumor recurrence of non-muscle invasive bladder cancer through STAT3/Twist1/P-glycoprotein signaling.
Cell Signal. 2015; 27(12):2515-23 [PubMed] Related Publications
There is a high frequency of tumor recurrence in non-muscle invasive bladder cancer (NMIBC) after transurethral resection and postoperative intravesical chemotherapy, however, the molecular mechanisms leading to the chemoresistance and tumor re-growth remain largely unknown. In this study, we observed a significant decrease of DAB2IP expression in high-grade and recurrent NMIBC specimens, which was negatively correlated with Twist1 expression and predicted a lower recurrence-free survival of patients. Mechanistically, DAB2IP could inhibit the phosphorylation and transactivation of STAT3, and then subsequently suppress the expression of Twist1 and its target gene P-glycoprotein, both of which were crucial for the pirarubicin chemoresistance and tumor re-growth of bladder cancer cells. Overall, this study reveals a new promising biomarker modulating the chemoresistance and tumor recurrence of NMIBC after bladder preservation surgery.

Wang J, Zhu X, Hu J, et al.
The positive feedback between Snail and DAB2IP regulates EMT, invasion and metastasis in colorectal cancer.
Oncotarget. 2015; 6(29):27427-39 [PubMed] Free Access to Full Article Related Publications
DAB2IP has been identified as a tumor suppressor in several cancers but its oncogenic role and transcriptionally regulatory mechanisms in the progression of colorectal carcinoma (CRC) remain unknown. In this study, DAB2IP was down-regulated in CRC tissues and a valuable prognostic marker for survival of CRC patients, especially in the late stage. Moreover, DAB2IP was sufficient to suppress proliferation, epithelial-mesenchymal transition (EMT), invasion and metastasis in CRC. Mechanically, the linear complex of EZH2/HDAC1/Snail contributed to DAB2IP silencing in CRC cells. The study further proved that the positive feedback loop between Snail and DAB2IP existed in CRC cells and DAB2IP was required for Snail-induced aggressive cell behaviors. Finally, DAB2IP correlated negatively with Snail and EZH2 expressions in CRC tissues. Our findings reveal the suppressive role and a novel regulatory mechanism of DAB2IP expression in the progression of CRC. DAB2IP may be a potential, novel therapeutic and prognostic target for clinical CRC patients.

Ji W, Li Y, He Y, et al.
AIP1 Expression in Tumor Niche Suppresses Tumor Progression and Metastasis.
Cancer Res. 2015; 75(17):3492-504 [PubMed] Free Access to Full Article Related Publications
Studies from tumor cells suggest that tumor-suppressor AIP1 inhibits epithelial-mesenchymal transition (EMT). However, the role of AIP1 in the tumor microenvironment has not been examined. We show that a global or vascular endothelial cell (EC)-specific deletion of the AIP1 gene in mice augments tumor growth and metastasis in melanoma and breast cancer models. AIP1-deficient vascular environment not only enhances tumor neovascularization and increases premetastatic niche formation, but also secretes tumor EMT-promoting factors. These effects from AIP1 loss are associated with increased VEGFR2 signaling in the vascular EC and could be abrogated by systemic administration of VEGFR2 kinase inhibitors. Mechanistically, AIP1 blocks VEGFR2-dependent signaling by directly binding to the phosphotyrosine residues within the activation loop of VEGFR2. Our data reveal that AIP1, by inhibiting VEGFR2-dependent signaling in tumor niche, suppresses tumor EMT switch, tumor angiogenesis, and tumor premetastatic niche formation to limit tumor growth and metastasis.

Xu Y, He J, Wang Y, et al.
miR-889 promotes proliferation of esophageal squamous cell carcinomas through DAB2IP.
FEBS Lett. 2015; 589(10):1127-35 [PubMed] Related Publications
MicroRNAs have been reported to play critical roles in various cancers, but there has been no study on the role of miR-889 in cancers. Here, we report that over-expression of miR-889 leads to rapid proliferation of EC109 and EC9706 cells in vitro and in vivo by inducing cells into S-phase. Using bioinformatics methods, DAB2IP was further confirmed to be a direct target of miR-889. In addition, the expression of DAB2IP, which was negatively correlated with that of miR-889, was significantly associated with clinicopathological features of ESCC patients. In conclusion, miR-889 is an important regulator in ESCC and both miR-889 and DAB2IP may serve as promising biomarkers and therapeutic targets in patients with ESCC.

Lechuga S, Baranwal S, Ivanov AI
Actin-interacting protein 1 controls assembly and permeability of intestinal epithelial apical junctions.
Am J Physiol Gastrointest Liver Physiol. 2015; 308(9):G745-56 [PubMed] Free Access to Full Article Related Publications
Adherens junctions (AJs) and tight junctions (TJs) are crucial regulators of the integrity and restitution of the intestinal epithelial barrier. The structure and function of epithelial junctions depend on their association with the cortical actin cytoskeleton that, in polarized epithelial cells, is represented by a prominent perijunctional actomyosin belt. The assembly and stability of the perijunctional cytoskeleton is controlled by constant turnover (disassembly and reassembly) of actin filaments. Actin-interacting protein (Aip) 1 is an emerging regulator of the actin cytoskeleton, playing a critical role in filament disassembly. In this study, we examined the roles of Aip1 in regulating the structure and remodeling of AJs and TJs in human intestinal epithelium. Aip1 was enriched at apical junctions in polarized human intestinal epithelial cells and normal mouse colonic mucosa. Knockdown of Aip1 by RNA interference increased the paracellular permeability of epithelial cell monolayers, decreased recruitment of AJ/TJ proteins to steady-state intercellular contacts, and attenuated junctional reassembly in a calcium-switch model. The observed defects of AJ/TJ structure and functions were accompanied by abnormal organization and dynamics of the perijunctional F-actin cytoskeleton. Moreover, loss of Aip1 impaired the apico-basal polarity of intestinal epithelial cell monolayers and inhibited formation of polarized epithelial cysts in 3-D Matrigel. Our findings demonstrate a previously unanticipated role of Aip1 in regulating the structure and remodeling of intestinal epithelial junctions and early steps of epithelial morphogenesis.

Zhang T, Shen Y, Chen Y, et al.
The ATM inhibitor KU55933 sensitizes radioresistant bladder cancer cells with DAB2IP gene defect.
Int J Radiat Biol. 2015; 91(4):368-78 [PubMed] Related Publications
PURPOSE: Our preliminary results showed that differentially expressed in ovarian cancer-2/disabled homolog 2 (DOC-2/DAB2) interactive protein (DAB2IP), a putative tumor suppressor gene, is down-regulated in bladder cancer (BCa) with aggressive phenotypes. In this study, we investigated how DAB2IP knockdown influenced BCa cell response to ionizing radiation (IR) and discussed possible ways to enhance cell radiosensitivity.
METHODS AND MATERIALS: The small interfering RNA (siRNA) system was implemented to inhibit endogenous DAB2IP expression in two human BCa cell lines, T24 and 5637. Cell sensitivity to IR alone or combined treatment was measured by a colony formation assay (CFA). Western blot was used to determine the phosphorylation levels of ataxia-telangiectasia mutated (ATM), catalytic subunit of the DNA-dependent protein kinase (DNA-PKcs) and related DNA damage repair (DDR) proteins. Immunofluorescence as well as a flow cytometry assay were employed to detect DNA double-strand break (DSB) repair and cell cycle distribution, respectively.
RESULTS: DAB2IP-knockdown of BCa cells (i.e., siDAB2IP) exhibit increased clonogenic survival in response to IR compared with control cells (i.e., siCON) expressing an endogenous level of DAB2IP. The mechanism in siDAB2IP cells could be explained by elevated ATM expression and activation, increased S phase cell distribution as well as faster DSB repair kinetics. 2-morpholin-4-yl-6-thianthren-1-yl-pyran-4-one (KU55933) significantly sensitized siDAB2IP cells to IR due to inhibition of the phosphorylation of ATM and its downstream targets following IR and slower DSB repair kinetics.
CONCLUSIONS: Loss of DAB2IP expression in BCa cells signifies their radioresistance. KU55933, which suppresses ATM phosphorylation upon irradiation, could be applied in the radiotherapy of BCa patients with a DAB2IP gene defect.

Tervasmäki A, Winqvist R, Jukkola-Vuorinen A, Pylkäs K
Recurrent CYP2C19 deletion allele is associated with triple-negative breast cancer.
BMC Cancer. 2014; 14:902 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Using a genome-wide approach, we have previously observed an increase in the frequency of rare copy number variants (CNVs) in familial and early-onset breast cancer cases when compared to controls. Moreover, the biological networks of the CNV disrupted genes differed between the two groups. Here, six of the previously observed CNVs were selected for further investigation. Four of these were singletons and disturbed the following genes: DCLRE1C, CASP3, DAB2IP and ITGA9, encoding proteins that are part of the TP53 and β-estradiol centered network. The two others were recurrent alleles and disrupted CDH19 and CYP2C19 genes. Of these, CDH19 encodes a cadherin functioning as a cell-cell adhesion receptor and CYP2C19 a CYP450 enzyme with a major function in estrogen catabolism.
METHODS: The exact breakpoints of the six previously observed CNV deletion alleles were defined by using qPCR, nested PCR and sequencing. The prevalence of these CNVs was investigated in 842 Northern Finnish breast cancer cases, unselected for family history of cancer and age at disease onset, as well as in 497 healthy female controls by using multiplex PCR. Also the association of the relatively common CDH19 and CYP2C19 deletion alleles with different clinical parameters was studied.
RESULTS: No significant differences in the carrier frequencies between cases and controls were found for any of the studied CNVs. However, the deletion in CYP2C19 showed a significant association with triple-negative breast cancer (p=0.021).
CONCLUSION: Our results indicate that inherited changes in CYP2C19 gene participating in estrogen catabolism have an influence on the molecular subtype of breast cancer.

Conway K, Edmiston SN, May R, et al.
DNA methylation profiling in the Carolina Breast Cancer Study defines cancer subclasses differing in clinicopathologic characteristics and survival.
Breast Cancer Res. 2014; 16(5):450 [PubMed] Free Access to Full Article Related Publications
INTRODUCTION: Breast cancer is a heterogeneous disease, with several intrinsic subtypes differing by hormone receptor (HR) status, molecular profiles, and prognosis. However, the role of DNA methylation in breast cancer development and progression and its relationship with the intrinsic tumor subtypes are not fully understood.
METHODS: A microarray targeting promoters of cancer-related genes was used to evaluate DNA methylation at 935 CpG sites in 517 breast tumors from the Carolina Breast Cancer Study, a population-based study of invasive breast cancer.
RESULTS: Consensus clustering using methylation (β) values for the 167 most variant CpG loci defined four clusters differing most distinctly in HR status, intrinsic subtype (luminal versus basal-like), and p53 mutation status. Supervised analyses for HR status, subtype, and p53 status identified 266 differentially methylated CpG loci with considerable overlap. Genes relatively hypermethylated in HR+, luminal A, or p53 wild-type breast cancers included FABP3, FGF2, FZD9, GAS7, HDAC9, HOXA11, MME, PAX6, POMC, PTGS2, RASSF1, RBP1, and SCGB3A1, whereas those more highly methylated in HR-, basal-like, or p53 mutant tumors included BCR, C4B, DAB2IP, MEST, RARA, SEPT5, TFF1, THY1, and SERPINA5. Clustering also defined a hypermethylated luminal-enriched tumor cluster 3 that gene ontology analysis revealed to be enriched for homeobox and other developmental genes (ASCL2, DLK1, EYA4, GAS7, HOXA5, HOXA9, HOXB13, IHH, IPF1, ISL1, PAX6, TBX1, SOX1, and SOX17). Although basal-enriched cluster 2 showed worse short-term survival, the luminal-enriched cluster 3 showed worse long-term survival but was not independently prognostic in multivariate Cox proportional hazard analysis, likely due to the mostly early stage cases in this dataset.
CONCLUSIONS: This study demonstrates that epigenetic patterns are strongly associated with HR status, subtype, and p53 mutation status and may show heterogeneity within tumor subclass. Among HR+ breast tumors, a subset exhibiting a gene signature characterized by hypermethylation of developmental genes and poorer clinicopathologic features may have prognostic value and requires further study. Genes differentially methylated between clinically important tumor subsets have roles in differentiation, development, and tumor growth and may be critical to establishing and maintaining tumor phenotypes and clinical outcomes.

Tsai YS, Lai CL, Lai CH, et al.
The role of homeostatic regulation between tumor suppressor DAB2IP and oncogenic Skp2 in prostate cancer growth.
Oncotarget. 2014; 5(15):6425-36 [PubMed] Free Access to Full Article Related Publications
Altered DAB2IP gene expression often detected in prostate cancer (PCa) is due to epigenetic silencing. In this study, we unveil a new mechanism leading to the loss of DAB2IP protein; an oncogenic S-phase kinase-associated protein-2 (Skp2) as E3 ubiquitin ligase plays a key regulator in DAB2IP degradation. In order to unveil the role of Skp2 in the turnover of DAB2IP protein, both prostate cell lines and prostate cancer specimens with a variety of molecular and cell biologic techniques were employed. We demonstrated that DAB2IP is regulated by Skp2-mediated proteasome degradation in the prostate cell lines. Further analyses identified the N-terminal DAB2IP containing the ubiquitination site. Immunohistochemical study exhibited an inverse correlation between DAB2IP and Skp2 protein expression in the prostate cancer tissue microarray. In contrast, DAB2IP can suppressSkp2 protein expression is mediated through Akt signaling. The reciprocal regulation between DAB2IP and Skp2 can impact on the growth of PCa cells. This reciprocal regulation between DAB2IP and Skp2 protein represents a unique homeostatic balance between tumor suppressor and oncoprotein in normal prostate epithelia, which is apparently altered in cancer cells. The outcome of this study has identified new potential targets for developing new therapeutic strategy for PCa.

Yun EJ, Baek ST, Xie D, et al.
DAB2IP regulates cancer stem cell phenotypes through modulating stem cell factor receptor and ZEB1.
Oncogene. 2015; 34(21):2741-52 [PubMed] Related Publications
Cancer stem cell (CSC), the primary source of cancer-initiating population, is involved in cancer recurrence and drug-resistant phenotypes. This study demonstrates that the loss of DAB2IP, a novel Ras-GTPase activating protein frequently found in many cancer types, is associated with CSC properties. Mechanistically, DAB2IP is able to suppress stem cell factor receptor (c-kit or CD117) gene expression by interacting with a newly identified silencer in the c-kit gene. Moreover, DAB2IP is able to inhibit c-kit-PI3K-Akt-mTOR signaling pathway that increases c-myc protein to activate ZEB1 gene expression leading to the elevated CSC phenotypes. An inverse correlation between CD117 or ZEB1 and DAB2IP is also found in clinical specimens. Similarly, Elevated expression of ZEB1 and CD117 are found in the prostate basal cell population of DAB2IP knockout mice. Our study reveals that DAB2IP has a critical role in modulating CSC properties via CD117-mediated ZEB1 signaling pathway.

Lai CH, Chang CS, Liu HH, et al.
Sensitization of radio-resistant prostate cancer cells with a unique cytolethal distending toxin.
Oncotarget. 2014; 5(14):5523-34 [PubMed] Free Access to Full Article Related Publications
Cytolethal distending toxin (CDT) produced by Campylobacter jejuni is a genotoxin that induces cell-cycle arrest and apoptosis in mammalian cells. Recent studies have demonstrated that prostate cancer (PCa) cells can acquire radio-resistance when DOC-2/DAB2 interactive protein (DAB2IP) is downregulated. In this study, we showed that CDT could induce cell death in DAB2IP-deficient PCa cells. A combination of CDT and radiotherapy significantly elicited cell death in DAB2IP-deficient PCa cells by inhibiting the repair of ionizing radiation (IR)-induced DNA double-strand break (DSB) during G2/M arrest, which is triggered by ataxia telangiectasia mutated (ATM)-dependent DNA damage checkpoint responses. We also found that CDT administration significantly increased the efficacy of radiotherapy in a xenograft mouse model. These results indicate that CDT can be a potent therapeutic agent for radio-resistant PCa.

Dai X, North BJ, Inuzuka H
Negative regulation of DAB2IP by Akt and SCFFbw7 pathways.
Oncotarget. 2014; 5(10):3307-15 [PubMed] Free Access to Full Article Related Publications
Deletion of ovarian carcinoma 2/disabled homolog 2 (DOC-2/DAB2) interacting protein (DAB2IP), is a tumor suppressor that serves as a scaffold protein involved in coordinately regulating cell proliferation, survival and apoptotic pathways. DAB2IP is epigenetically down-regulated in a variety of tumors through the action of the histone methyltransferase EZH2. Although DAB2IP is transcriptionally down-regulated in a variety of tumors, it remains unclear if other mechanisms contribute to functional inactivation of DAB2IP. Here we demonstrate that DAB2IP can be functionally down-regulated by two independent mechanisms. First, we identified that Akt1 can phosphorylate DAB2IP on S847, which regulates the interaction between DAB2IP and its effector molecules H-Ras and TRAF2. Second, we demonstrated that DAB2IP can be degraded in part through ubiquitin-proteasome pathway by SCF(Fbw7). DAB2IP harbors two Fbw7 phosho-degron motifs, which can be regulated by the kinase, CK1δ. Our data hence indicate that in addition to epigenetic down-regulation, two additional pathways can functional inactivate DAB2IP. Given that DAB2IP has previously been identified to possess direct causal role in tumorigenesis and metastasis, our data indicate that a variety of pathways may pass through DAB2IP to govern cancer development, and therefore highlight DAB2IP agonists as potential therapeutic approaches for future anti-cancer drug development.

Maertens O, Cichowski K
An expanding role for RAS GTPase activating proteins (RAS GAPs) in cancer.
Adv Biol Regul. 2014; 55:1-14 [PubMed] Related Publications
The RAS pathway is one of the most commonly deregulated pathways in human cancer. Mutations in RAS genes occur in nearly 30% of all human tumors. However in some tumor types RAS mutations are conspicuously absent or rare, despite the fact that RAS and downstream effector pathways are hyperactivated. Recently, RAS GTPase Activating Proteins (RAS GAPs) have emerged as an expanding class of tumor suppressors that, when inactivated, provide an alternative mechanism of activating RAS. RAS GAPs normally turn off RAS by catalyzing the hydrolysis of RAS-GTP. As such, the loss of a RAS GAP would be expected to promote excessive RAS activation. Indeed, this is the case for the NF1 gene, which plays an established role in a familial tumor predisposition syndrome and a variety of sporadic cancers. However, there are 13 additional RAS GAP family members in the human genome. We are only now beginning to understand why there are so many RAS GAPs, how they differentially function, and what their potential role(s) in human cancer are. This review will focus on our current understanding of RAS GAPs in human disease and will highlight important outstanding questions.

Ding L, Chen S, Liu P, et al.
CBP loss cooperates with PTEN haploinsufficiency to drive prostate cancer: implications for epigenetic therapy.
Cancer Res. 2014; 74(7):2050-61 [PubMed] Free Access to Full Article Related Publications
Despite the high incidence and mortality of prostate cancer, the etiology of this disease is not fully understood. In this study, we develop functional evidence for CBP and PTEN interaction in prostate cancer based on findings of their correlate expression in the human disease. Cbp(pc-/-);Pten(pc+/-) mice exhibited higher cell proliferation in the prostate and an early onset of high-grade prostatic intraepithelial neoplasia. Levels of EZH2 methyltransferase were increased along with its Thr350 phosphorylation in both mouse Cbp(-/-); Pten(+/-) and human prostate cancer cells. CBP loss and PTEN deficiency cooperated to trigger a switch from K27-acetylated histone H3 to K27-trimethylated bulk histones in a manner associated with decreased expression of the growth inhibitory EZH2 target genes DAB2IP, p27(KIP1), and p21(CIP1). Conversely, treatment with the histone deacetylase inhibitor panobinostat reversed this switch, in a manner associated with tumor suppression in Cbp(pc-/-);Pten(pc+/-) mice. Our findings show how CBP and PTEN interact to mediate tumor suppression in the prostate, establishing a central role for histone modification in the etiology of prostate cancer and providing a rationale for clinical evaluation of epigenetic-targeted therapy in patients with prostate cancer.

Tamgue O, Chai CS, Hao L, et al.
Triptolide inhibits histone methyltransferase EZH2 and modulates the expression of its target genes in prostate cancer cells.
Asian Pac J Cancer Prev. 2013; 14(10):5663-9 [PubMed] Related Publications
The histone methyltransferase EZH2 (enhancer of zeste homolog 2) plays critical roles in prostate cancer (PCa) development and is a potential target for PCa treatment. Triptolide possesses anti-tumor activity, but it is unknown whether its therapeutic effect relates with EZH2 in PCa. Here we described EZH2 as a target for Triptolide in PCa cells. Our data showed that Triptolide suppressed PCa cell growth and reduced the expression of EZH2. Overexpression of EZH2 attenuated the Triptolide induced cell growth inhibition. Moreover, Triptolide treatment of PC-3 cells resulted in elevated mRNA levels of target genes (ADRB2, CDH1, CDKN2A and DAB2IP) negatively regulated by EZH2 as well as reduced mRNA levelsan of EZH2 positively regulated gene (cyclin D1). Our findings suggest the PCa cell growth inhibition mediated by Triptolide might be associated with downregulation of EZH2 expression and the subsequent modulation of target genes.

Mygatt JG, Singhal A, Sukumar G, et al.
Oncogenic herpesvirus HHV-8 promotes androgen-independent prostate cancer growth.
Cancer Res. 2013; 73(18):5695-708 [PubMed] Related Publications
Mechanisms underlying progression to androgen-independent prostate cancer following radical ablation therapy remain poorly defined. Although intraprostatic infections have been highlighted as potential cofactors, pathogen influences on pathways that support tumor regrowth are not known. To explore this provocative concept, we derived androgen-sensitive and -insensitive prostate epithelial cells persistently infected with human herpesvirus 8 (HHV-8), an oncogenic herpesvirus that has been detected in normal prostate epithelium, prostate adenocarcinoma, and biologic fluids of patients with prostate cancer, to explore its effects on transition to hormone-refractory disease. Strikingly, we found that HHV-8 infection of androgen-sensitive prostate cancer cells conferred the capacity for androgen-independent growth. This effect was associated with altered expression and transcriptional activity of the androgen receptor (AR). However, HHV-8 infection bypassed AR signaling by promoting enhancer of zeste homolog 2 (EZH2)-mediated epigenetic silencing of tumor-suppressor genes, including MSMB and DAB2IP that are often inactivated in advanced disease. Furthermore, we found that HHV-8 triggered epithelial-to-mesenchymal transition. Although HHV-8 has not been linked etiologically to prostate cancer, virologic outcomes revealed by our study provide mechanistic insight into how intraprostatic infections could constitute risk for progression to androgen-independent metastatic disease where EZH2 has been implicated. Taken together, our findings prompt further evaluations of the relationship between HHV-8 infections and risk of advanced prostate cancer.

Wu K, Xie D, Zou Y, et al.
The mechanism of DAB2IP in chemoresistance of prostate cancer cells.
Clin Cancer Res. 2013; 19(17):4740-9 [PubMed] Free Access to Full Article Related Publications
PURPOSE: The docetaxel-based chemotherapy is the standard of care for castration-resistant prostate cancer (CRPC), inevitably, patients develop resistance and decease. Until now, the mechanism and predictive marker for chemoresistance are poorly understood.
EXPERIMENTAL DESIGN: Immortalized normal prostate and cancer cell lines stably manipulated with different DAB2IP expression levels were used and treated with chemotherapeutic drugs commonly used in prostate cancer therapy. Cell proliferation was measured using MTT assay; Western blot, quantitative PCR, and luciferase reporter assays were used to analyze Clusterin gene regulation by DAB2IP. Immunohistochemical analysis was conducted for evaluating DAB2IP, Clusterin and Egr-1 expression in human prostate cancer tissue.
RESULTS: DAB2IP Knockdown (KD) cells exhibited resistance to several chemotherapeutic drugs, whereas increased DAB2IP in C4-2 cells restored the drug sensitivity. Parallel, DAB2IP KD cells exhibited higher expression of Clusterin, an antiapoptotic factor, whereas elevated DAB2IP in C4-2 cells decreased Clusterin expression. Functionally, knocking down Clusterin by short-hairpin RNA or antisense oligonucleotide OGX-011 decreased drug resistance, whereas overexpressing Clusterin in C4-2 D2 enhanced drug resistance. Mechanistically, DAB2IP blocked the cross-talk between Wnt/β-catenin and IGF-I signaling, leading to the suppression of Egr-1 that is responsible for Clusterin expression. A similar result was observed in the prostate of DAB2IP knockout animals. In addition, we observed a significantly inverse correlation between DAB2IP and Egr-1 or Clusterin expression from clinical tissue microarray.
CONCLUSIONS: This study unveils a new regulation of the Egr-1/Clusterin signaling network by DAB2IP. Loss of DAB2IP expression in CRPC cells signifies their chemoresistance. Clusterin is a key target for developing more effective CRPC therapy.

Wu K, Liu J, Tseng SF, et al.
The role of DAB2IP in androgen receptor activation during prostate cancer progression.
Oncogene. 2014; 33(15):1954-63 [PubMed] Related Publications
Altered androgen-receptor (AR) expression and/or constitutively active AR are commonly associated with prostate cancer (PCa) progression. Targeting AR remains a focal point for designing new strategy of PCa therapy. Here, we have shown that DAB2IP, a novel tumor suppressor in PCa, can inhibit AR-mediated cell growth and gene activation in PCa cells via distinct mechanisms. DAB2IP inhibits the genomic pathway by preventing AR nuclear translocation or phosphorylation and suppresses the non-genomic pathway via its unique functional domain to inactivate c-Src. Also, DAB2IP is capable of suppressing AR activation in an androgen-independent manner. In addition, DAB2IP can inhibit several AR splice variants showing constitutive activity in PCa cells. In DAB2IP(-/-) mice, the prostate gland exhibits hyperplastic epithelia, in which AR becomes more active. Consistently, DAB2IP expression inversely correlates with AR activation status particularly in recurrent or metastatic PCa patients. Taken together, DAB2IP is a unique intrinsic AR modulator in normal cells, and likely can be further developed into a therapeutic agent for PCa.

Duan YF, Li DF, Liu YH, et al.
Decreased expression of DAB2IP in pancreatic cancer with wild-type KRAS.
Hepatobiliary Pancreat Dis Int. 2013; 12(2):204-9 [PubMed] Related Publications
BACKGROUND: KRAS mutation plays an important role in the pathogenesis of pancreatic cancer. However, the role of wild-type KRAS in the progression of pancreatic cancer remains unknown. The present study was to investigate the expression of the Ras GTPase activating protein (DAB2IP) in pancreatic cancer and its clinical significance.
METHODS: The expression of DAB2IP in pancreatic cancer cell lines and normal human pancreatic ductal epithelial cells was analyzed by Western blotting and real-time quantitative reverse transcription-PCR (qRT-PCR). The KRAS mutational types of pancreatic cancer tissues obtained from pancreatic cancer patients (n=20) were also analyzed. Subsequently, DAB2IP expression was detected in pancreatic cancer tissues, adjacent and normal pancreatic tissues (n=2) by immunohistochemistry, and the relationship between DAB2IP expression and the clinical characteristics of patients was evaluated.
RESULTS: Western blotting and qRT-PCR results showed that DAB2IP expression in pancreatic cancer cells with wild-type KRAS was lower than that in those with mutation-type KRAS and normal human pancreatic ductal epithelial cells (P<0.05). Immunohistochemistry showed that DAB2IP expression was lower in pancreatic cancer tissues than that in adjacent and normal pancreatic tissues (Z=-4.000, P=0.000). DAB2IP expression was lower in pancreatic cancer patients with the wild-type KRAS gene than that in those with KRAS mutations (WilcoxonW=35.000, P=0.042). Furthermore, DAB2IP expression in patients with perineurial invasion was lower than that in those without invasion (WilcoxonW=71.500, P=0.028). DAB2IP expression was lower in patients with more advanced stage than that in those with early clinical stage (WilcoxonW=54.000, P=0.002).
CONCLUSIONS: DAB2IP expression was reduced in patients with pancreatic cancer compared with those with no cancer. DAB2IP expression was correlated with the KRAS gene, perineurial invasion and clinical stage of the disease. Our data indicated that DAP2IP expression can be used as a potential prognostic indicator and a promising molecular target for therapeutic intervention in patients with pancreatic cancer.

Yu L, Tumati V, Tseng SF, et al.
DAB2IP regulates autophagy in prostate cancer in response to combined treatment of radiation and a DNA-PKcs inhibitor.
Neoplasia. 2012; 14(12):1203-12 [PubMed] Free Access to Full Article Related Publications
Radiation therapy (RT) is an effective strategy for the treatment of localized prostate cancer (PCa) as well as local invasion. However, some locally advanced cancers develop radiation resistance and recur after therapy; therefore, the development of radiation-sensitizing compounds is essential for treatment of these tumors. DOC-2/DAB2 interactive protein (DAB2IP), which is a novel member of the Ras-GTPase activating protein family and a regulator of phosphatidylinositol 3-kinase-Akt activity, is often downregulated in aggressive PCa. Our previous studies have shown that loss of DAB2IP results in radioresistance in PCa cells primarily because of accelerated DNA double-strand break (DSB) repair kinetics, robust G(2)/M checkpoint control, and evasion of apoptosis. A novel DNA-PKcs inhibitor NU7441 can significantly enhance the effect of radiation in DAB2IP-deficient PCa cells. This enhanced radiation sensitivity after NU7441 treatment is primarily due to delayed DNA DSB repair. More significantly, we found that DAB2IP-deficient PCa cells show dramatic induction of autophagy after treatment with radiation and NU7441. However, restoring DAB2IP expression in PCa cells resulted in decreased autophagy-associated proteins, such as LC3B and Beclin 1, as well as decreased phosphorylation of S6K and mammalian target of rapamycin (mTOR). Furthermore, the presence of DAB2IP in PCa cells can lead to more apoptosis in response to combined treatment of NU7441 and ionizing radiation. Taken together, NU7441 is a potent radiosensitizer in aggressive PCa cells and DAB2IP plays a critical role in enhancing PCa cell death after combined treatment with NU7441 and radiation.

Xu S, Zhou Y, Du WD, et al.
Association of the variant rs2243421 of human DOC-2/DAB2 interactive protein gene (hDAB2IP) with gastric cancer in the Chinese Han population.
Gene. 2013; 515(1):200-4 [PubMed] Related Publications
Human DOC-2/DAB2 interactive protein (hDAB2IP) gene is a novel member of the Ras GTPase-activating family and has been demonstrated to be a tumor-suppressor gene that inhibits cell survival and proliferation and induces cell apoptosis. It was reported that the expression level of hDAB2IP in gastric cancer tissue was highly correlated with tumor progression, however, whether hDAB2IP genetic variants are associated with the risk of gastric cancer remains yet unknown. In this case-control study, we conducted a genetic analysis for hDAB2IP variants in 311 patients with gastric cancer and 425 controls from the Chinese Han population. We found that the SNP rs2243421 of hDAB2IP gene with the minor allele C significantly revealed strong association with decreased gastric cancer susceptibility (P=0.007, adjusted odds ratio [OR]=0.734, 95%CI=0.586-0.919). Haplotypes rs2243421 and rs10985332 (HaploType: CC, P=0.012, aOR=0.760) and haplotypes rs2243421 and rs555996 (HaploType: CG, P=0.034, aOR=0.788) represented the decreased risk of gastric cancer, respectively. On the contrary, rs2243421 and rs555996 showed an elevated susceptibility (HaploType: TG, P=0.010, aOR=1.320). Our results for the first time provided new insight into susceptibility factors of hDAB2IP gene variants in carcinogenesis of gastric cancer.

Smits M, van Rijn S, Hulleman E, et al.
EZH2-regulated DAB2IP is a medulloblastoma tumor suppressor and a positive marker for survival.
Clin Cancer Res. 2012; 18(15):4048-58 [PubMed] Related Publications
PURPOSE: Medulloblastoma is the most common malignant brain tumor in children. Despite recent improvements, the molecular mechanisms driving medulloblastoma are not fully understood and further elucidation could provide cues to improve outcome prediction and therapeutic approaches.
EXPERIMENTAL DESIGN: Here, we conducted a meta-analysis of mouse and human medulloblastoma gene expression data sets, to identify potential medulloblastoma tumor suppressor genes.
RESULTS: We identified DAB2IP, a member of the RAS-GTPase-activating protein family (RAS GAP), and showed that DAB2IP expression is repressed in medulloblastoma by EZH2-induced trimethylation. Moreover, we observed that reduced DAB2IP expression correlates significantly with a poor overall survival of patients with medulloblastoma, independent of metastatic stage. Finally, we showed that ectopic DAB2IP expression enhances stress-induced apoptosis in medulloblastoma cells and that reduced expression of DAB2IP in medulloblastoma cells conveys resistance to irradiation-induced cell death.
CONCLUSION: These results suggest that repression of DAB2IP may at least partly protect medulloblastoma cells from apoptotic cell death. Moreover, DAB2IP may represent a molecular marker to distinguish patients with medulloblastoma at high risk from those with a longer survival prognosis.

Dang X, Ma A, Yang L, et al.
MicroRNA-26a regulates tumorigenic properties of EZH2 in human lung carcinoma cells.
Cancer Genet. 2012; 205(3):113-23 [PubMed] Related Publications
MicroRNAs (miRNAs) are a class of 21-23 nucleotide RNA molecules that play critical roles in the regulation of various cancers, including human lung cancer. Among them, miR-26a has been identified as a tumor-related regulator in several cancers, but its pathophysiologic properties and correlation with the development of human lung cancer remain unclear. In this study, it was determined that miR-26a expression is clearly down-regulated in human lung cancer tissues relative to normal tissues. Meanwhile, the overexpression of miR-26a in the A549 human lung cancer cell line dramatically inhibited cell proliferation, blocked G1/S phase transition, induced apoptosis, and inhibited cell metastasis and invasion in vitro. In contrast, a miR-26a inhibitor was used to transfect A549 cells, and the inhibition of endogenous miR-26a promoted cell metastasis and invasion. In addition, miR-26a expression inhibited the expression of enhancer of zeste homolog 2 (EZH2) and transactivated downstream target genes, including disabled homolog 2 (Drosophila) interacting protein gene (DAB2IP) and human Runt-related transcription factor 3 (RUNX3), which suggests that EZH2 is a potential target of miR-26a as previously reported. In conclusion, miR-26a plays an important role as an anti-oncogene in the molecular mechanism of human lung cancer and could potentially be used for the treatment of lung cancer.

Zhang X, Li N, Li X, et al.
Low expression of DAB2IP contributes to malignant development and poor prognosis in hepatocellular carcinoma.
J Gastroenterol Hepatol. 2012; 27(6):1117-25 [PubMed] Related Publications
BACKGROUND AND AIM: DOC-2/DAB2 interactive protein gene (DAB2IP) is a novel member of the Ras GTPase-activating protein family and plays a tumor suppressive role in cancer progression, but its function in hepatocellular carcinoma (HCC) remains unclear. This aims of this study were to analyze the clinicopathological features of DAB2IP expression in HCC, and to determine the effect of DAB2IP on HCC cell behaviors in vitro.
METHODS: The expression of DAB2IP was detected in hepatocyte cell line and HCC cell lines by real-time reverse transcription-polymerase chain reaction and western blot. DAB2IP expression was then examined in 120 cases of clinical paraffin-embedded HCC tissue by immunohistochemistry (IHC). 3-(4,5)-dimethylthiahiazo (-z-y1)-3,5-di- phenytetrazoliumromide (MTT) method and in vitro invasive assay were finally performed to evaluate the effect of DAB2IP depletion on cell proliferation or invasion of HCC cells.
RESULTS: DAB2IP expression was lower in HCC cell lines or tissues than in hepatocyte cell lines, adjacent cirrhotic livers or normal livers (P < 0.05). Its expression was positively correlated with tumor size (P = 0.01). Patients with lower DAB2IP expression had shorter overall survival time (P = 0.013). DAB2IP suppresses proliferation and invasion of HCC cells in vitro.
CONCLUSION: DAB2IP is a valuable marker for progression of HCC patients. Downregulation of DAB2IP is associated with poor prognosis in HCC patients. DAB2IP silence alone is sufficient to promote HCC cell proliferation and invasion in vitro.

Yang L, Li Y, Ling X, et al.
A common genetic variant (97906C>A) of DAB2IP/AIP1 is associated with an increased risk and early onset of lung cancer in Chinese males.
PLoS One. 2011; 6(10):e26944 [PubMed] Free Access to Full Article Related Publications
DOC-2/DAB2 interactive protein (DAB2IP) is a novel identified tumor suppressor gene that inhibits cell growth and facilitates cell apoptosis. One genetic variant in DAB2IP gene was reported to be associated with an increased risk of aggressive prostate cancer recently. Since DAB2IP involves in the development of lung cancer and low expression of DAB2IP are observed in lung cancer, we hypothesized that the variations in DAB2IP gene can increase the genetic susceptibility to lung cancer. In a case-control study of 1056 lung cancer cases and 1056 sex and age frequency-matched cancer-free controls, we investigated the association between two common polymorphisms in DAB2IP gene (-1420T>G, rs7042542; 97906C>A, rs1571801) and the risk of lung cancer. We found that compared with the 97906CC genotypes, carriers of variant genotypes (97906AC+AA) had a significant increased risk of lung cancer (adjusted odds ratio [OR] = 1.33, 95%CI = 1.04-1.70, P = 0.023) and the number of variant (risk) allele worked in a dose-response manner (P(trend) = 0.0158). Further stratification analysis showed that the risk association was more pronounced in subjects aged less than 60 years old, males, non-smokers, non-drinkers, overweight groups and in those with family cancer history in first or second-degree relatives, and the 97906A interacted with overweight on lung cancer risk. We further found the number of risk alleles (97906A allele) were negatively correlated with early diagnosis age of lung cancer in male patients (P = 0.003). However, no significant association was observed on the -1420T>G polymorphism. Our data suggested that the 97906A variant genotypes are associated with the increased risk and early onset of lung cancer, particularly in males.

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