SETD2

Gene Summary

Gene:SETD2; SET domain containing 2
Aliases: HYPB, SET2, HIF-1, HIP-1, KMT3A, HBP231, HSPC069, p231HBP
Location:3p21.31
Summary:Huntington's disease (HD), a neurodegenerative disorder characterized by loss of striatal neurons, is caused by an expansion of a polyglutamine tract in the HD protein huntingtin. This gene encodes a protein belonging to a class of huntingtin interacting proteins characterized by WW motifs. This protein is a histone methyltransferase that is specific for lysine-36 of histone H3, and methylation of this residue is associated with active chromatin. This protein also contains a novel transcriptional activation domain and has been found associated with hyperphosphorylated RNA polymerase II. [provided by RefSeq, Aug 2008]
Databases:OMIM, VEGA, HGNC, Ensembl, GeneCard, Gene
Protein:histone-lysine N-methyltransferase SETD2
HPRD
Source:NCBIAccessed: 17 August, 2015

Ontology:

What does this gene/protein do?
Show (23)

Cancer Overview

Research Indicators

Publications Per Year (1990-2015)
Graph generated 17 August 2015 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.

  • Genome, Human
  • VHL
  • DNA Mutational Analysis
  • Exome
  • Leukaemia
  • Tumor Suppressor Proteins
  • Staging
  • Histones
  • Mutation
  • Histone Demethylases
  • Transcription Factors
  • Epigenetics
  • DNA Methylation
  • Chromatin Assembly and Disassembly
  • Molecular Targeted Therapy
  • Cancer RNA
  • Genetic Predisposition
  • p53 Protein
  • Kidney Cancer
  • Neoplastic Cell Transformation
  • Methylation
  • Childhood Cancer
  • Oxidoreductases, N-Demethylating
  • Nuclear Proteins
  • AKT1
  • Renal Cell Carcinoma
  • Cancer Gene Expression Regulation
  • Stomach Cancer
  • Ubiquitin Thiolesterase
  • Phenotype
  • DNA Copy Number Variations
  • Tumor Suppressor Gene
  • Histone-Lysine N-Methyltransferase
  • Point Mutation
  • Chromosome 3
  • Single Nucleotide Polymorphism
  • Chromatin
  • Gene Silencing
  • Signal Transduction
Tag cloud generated 17 August, 2015 using data from PubMed, MeSH and CancerIndex

Specific Cancers (3)

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: SETD2 (cancer-related)

Ye Q, Lei L, Aili AX
Identification of potential targets for ovarian cancer treatment by systematic bioinformatics analysis.
Eur J Gynaecol Oncol. 2015; 36(3):283-9 [PubMed] Related Publications
PURPOSE OF INVESTIGATION: To provide a systematic overview to understand the mechanism of ovarian cancer.
MATERIALS AND METHODS: Data of GSE14407 downloaded from Gene Expression Omnibus (GEO) database and differentially expressed genes (DEGs) were identified. Gene ontology and pathway enrichment analysis were performed by Database for Annotation, Visualization and Integrated Discovery (DAVID). Furthermore, the authors constructed the protein-protein interaction (PPI) network and co-expression networks by Cytoscape.
RESULTS: A total 1,442 genes were identified to be differentially expressed. Regulatory effects of DEGs mainly focused on cell cycle, transcription regulation, and cellular protein metabolic process. Significant pathways were determined to be p53 signaling pathway, amino sugar, and nucleotide sugar metabolism. The most significant transcription factor was aryl hydrocarbon receptor nuclear translocator (ARNT). Abnormal spindle-like microcephaly-associated protein (ASPM), Aurora kinase (AURKA), Cyclin-A2 (CCNA2), G2/mitotic-specific cyclin-B1, (CCNB1), and Cyclin-dependent kinase 1 (CDK1) were significant nodes in PPI network.
CONCLUSION: The significant genes and pathways show potential targets for the treatment of ovarian cancer.

Geczova L, Soltysova A, Gecz J, et al.
Avascular necrosis of bone in childhood cancer patients: a possible role of genetic susceptibility.
Bratisl Lek Listy. 2015; 116(5):289-95 [PubMed] Related Publications
With the increasing number of paediatric cancer patients and with their prolonged survival, the evidence of a number of serious complications induced by anticancer therapy is rising. Osteonecrosis (ON) of bone is one of these treatment-related effects with a multifactorial pathogenesis. In the past few years, several polymorphisms of candidate genes with possible role in development of this disorder were studied.We summarized potential risk factors leading to increased susceptibility to osteonecrosis of bone development in cancer patients during childhood and to present current knowledge in the field of genetic aspects of this condition (Ref. 86).

Marín-Ramos NI, Alonso D, Ortega-Gutiérrez S, et al.
New inhibitors of angiogenesis with antitumor activity in vivo.
J Med Chem. 2015; 58(9):3757-66 [PubMed] Related Publications
Angiogenesis is a requirement for the sustained growth and proliferation of solid tumors, and the development of new compounds that induce a sustained inhibition of the proangiogenic signaling generated by tumor hypoxia still remains as an important unmet need. In this work, we describe a new antiangiogenic compound (22) that inhibits proangiogenic signaling under hypoxic conditions in breast cancer cells. Compound 22 blocks the MAPK pathway, impairs cellular migration under hypoxic conditions, and regulates a set of genes related to angiogenesis. These responses are mediated by HIF-1α, since the effects of compound 22 mostly disappear when its expression is knocked-down. Furthermore, administration of compound 22 in a xenograft model of breast cancer produced tumor growth reductions ranging from 46 to 55% in 38% of the treated animals without causing any toxic side effects. Importantly, in the responding tumors, a significant reduction in the number of blood vessels was observed, further supporting the mechanism of action of the compound. These findings provide a rationale for the development of new antiangiogenic compounds that could eventually lead to new drugs suitable for the treatment of some types of tumors either alone or in combination with other agents.

Fernandez EV, Reece KM, Ley AM, et al.
Dual targeting of the androgen receptor and hypoxia-inducible factor 1α pathways synergistically inhibits castration-resistant prostate cancer cells.
Mol Pharmacol. 2015; 87(6):1006-12 [PubMed] Article available free on PMC after 01/12/2015 Related Publications
Enzalutamide is a potent second-generation androgen receptor (AR) antagonist with activity in metastatic castrate-resistant prostate cancer (CRPC). Although enzalutamide is initially effective, disease progression inevitably ensues with the emergence of resistance. Intratumoral hypoxia is also associated with CRPC progression and treatment resistance. Given that both AR and hypoxia inducible factor-1 α (HIF-1α) are key regulators of these processes, dual targeting of both signaling axes represents an attractive therapeutic approach. Crosstalk of the AR and HIF-1α signaling pathways were examined in prostate cancer cell lines (LNCaP, 22Rv1) with assays measuring the effect of androgen and hypoxia on AR-dependent and hypoxia-inducible gene transcription, protein expression, cell proliferation, and apoptosis. HIF-1α inhibition was achieved by siRNA silencing HIF-1α or via chetomin, a disruptor of HIF-1α-p300 interactions. In prostate cancer cells, the gene expression of AR targets (KLK3, FKBP5, TMPRSS2) was repressed by HIF-signaling; conversely, specific HIF-1α target expression was induced by dihydrotestosterone-mediated AR signaling. Treatment of CRPC cells with enzalutamide or HIF-1α inhibition attenuated AR-regulated and HIF-1α-mediated gene transcription. The combination of enzalutamide and HIF-1α inhibition was more effective than either treatment alone. Similarly, the combination also reduced vascular endothelial growth factor protein levels. HIF-1α siRNA synergistically enhanced the inhibitory effect of enzalutamide on cell growth in LNCaP and enzalutamide-resistant 22Rv1 cells via increased enzalutamide-induced apoptosis. In conclusion, the combination of enzalutamide with HIF-1α inhibition resulted in synergistic inhibition of AR-dependent and gene-specific HIF-dependent expression and prostate cancer cell growth.

Kovac M, Navas C, Horswell S, et al.
Recurrent chromosomal gains and heterogeneous driver mutations characterise papillary renal cancer evolution.
Nat Commun. 2015; 6:6336 [PubMed] Article available free on PMC after 01/12/2015 Related Publications
Papillary renal cell carcinoma (pRCC) is an important subtype of kidney cancer with a problematic pathological classification and highly variable clinical behaviour. Here we sequence the genomes or exomes of 31 pRCCs, and in four tumours, multi-region sequencing is undertaken. We identify BAP1, SETD2, ARID2 and Nrf2 pathway genes (KEAP1, NHE2L2 and CUL3) as probable drivers, together with at least eight other possible drivers. However, only ~10% of tumours harbour detectable pathogenic changes in any one driver gene, and where present, the mutations are often predicted to be present within cancer sub-clones. We specifically detect parallel evolution of multiple SETD2 mutations within different sub-regions of the same tumour. By contrast, large copy number gains of chromosomes 7, 12, 16 and 17 are usually early, monoclonal changes in pRCC evolution. The predominance of large copy number variants as the major drivers for pRCC highlights an unusual mode of tumorigenesis that may challenge precision medicine approaches.

Dulloo I, Phang BH, Othman R, et al.
Hypoxia-inducible TAp73 supports tumorigenesis by regulating the angiogenic transcriptome.
Nat Cell Biol. 2015; 17(4):511-23 [PubMed] Related Publications
The functional significance of the overexpression of unmutated TAp73, a homologue of the tumour suppressor p53, in multiple human cancers is unclear, but raises the possibility of unidentified roles in promoting tumorigenesis. We show here that TAp73 is stabilized by hypoxia, a condition highly prevalent in tumours, through HIF-1α-mediated repression of the ubiquitin ligase Siah1, which targets TAp73 for degradation. Consequently, TAp73-deficient tumours are less vascular and reduced in size, and conversely, TAp73 overexpression leads to increased vasculature. Moreover, we show that TAp73 is a critical regulator of the angiogenic transcriptome and is sufficient to directly activate the expression of several angiogenic genes.  Finally, expression of TAp73 positively correlates with these angiogenic genes in several human tumours, and the angiogenic gene signature is sufficient to segregate the TAp73(Hi)- from TAp73(Low)-expressing tumours. These data demonstrate a pro-angiogenic role for TAp73 in supporting tumorigenesis, providing a rationale for its overexpression in cancers.

Albers J, Danzer C, Rechsteiner M, et al.
A versatile modular vector system for rapid combinatorial mammalian genetics.
J Clin Invest. 2015; 125(4):1603-19 [PubMed] Article available free on PMC after 01/12/2015 Related Publications
Here, we describe the multiple lentiviral expression (MuLE) system that allows multiple genetic alterations to be introduced simultaneously into mammalian cells. We created a toolbox of MuLE vectors that constitute a flexible, modular system for the rapid engineering of complex polycistronic lentiviruses, allowing combinatorial gene overexpression, gene knockdown, Cre-mediated gene deletion, or CRISPR/Cas9-mediated (where CRISPR indicates clustered regularly interspaced short palindromic repeats) gene mutation, together with expression of fluorescent or enzymatic reporters for cellular assays and animal imaging. Examples of tumor engineering were used to illustrate the speed and versatility of performing combinatorial genetics using the MuLE system. By transducing cultured primary mouse cells with single MuLE lentiviruses, we engineered tumors containing up to 5 different genetic alterations, identified genetic dependencies of molecularly defined tumors, conducted genetic interaction screens, and induced the simultaneous CRISPR/Cas9-mediated knockout of 3 tumor-suppressor genes. Intramuscular injection of MuLE viruses expressing oncogenic H-RasG12V together with combinations of knockdowns of the tumor suppressors cyclin-dependent kinase inhibitor 2A (Cdkn2a), transformation-related protein 53 (Trp53), and phosphatase and tensin homolog (Pten) allowed the generation of 3 murine sarcoma models, demonstrating that genetically defined autochthonous tumors can be rapidly generated and quantitatively monitored via direct injection of polycistronic MuLE lentiviruses into mouse tissues. Together, our results demonstrate that the MuLE system provides genetic power for the systematic investigation of the molecular mechanisms that underlie human diseases.

Jeon YK, Park SG, Choi IW, et al.
Cancer cell-associated cytoplasmic B7-H4 is induced by hypoxia through hypoxia-inducible factor-1α and promotes cancer cell proliferation.
Biochem Biophys Res Commun. 2015; 459(2):277-83 [PubMed] Related Publications
Aberrant B7-H4 expression in cancer tissues serves as a novel prognostic biomarker for poor survival in patients with cancer. However, the factor(s) that induce cancer cell-associated B7-H4 remain to be fully elucidated. We herein demonstrate that hypoxia upregulates B7-H4 transcription in primary CD138(+) multiple myeloma cells and cancer cell lines. In support of this finding, analysis of the Multiple Myeloma Genomics Portal (MMGP) data set revealed a positive correlation between the mRNA expression levels of B7-H4 and the endogenous hypoxia marker carbonic anhydrogenase 9. Hypoxia-induced B7-H4 expression was detected in the cytoplasm, but not in cancer cell membranes. Chromatin immunoprecipitation analysis demonstrated binding of hypoxia-inducible factor-1α (HIF-1α) to proximal hypoxia-response element (HRE) sites within the B7-H4 promoter. Knockdown of HIF-1α and pharmacological inhibition of HIF-1α diminished B7-H4 expression. Furthermore, knockdown of cytoplasmic B7-H4 in MCF-7 decreased the S-phase cell population under hypoxia. Finally, MMGP analysis revealed a positive correlation between the transcript levels of B7-H4 and proliferation-related genes including MKI67, CCNA1, and Myc in several patients with multiple myeloma. Our results provide insight into the mechanisms underlying B7-H4 upregulation and its role in cancer cell proliferation in a hypoxic tumor microenvironment.

Yang SY, Song BQ, Dai SL, et al.
Effects of hypoxia-inducible factor-1α silencing on drug resistance of human pancreatic cancer cell line Patu8988/5-Fu.
Hepatogastroenterology. 2014 Nov-Dec; 61(136):2395-401 [PubMed] Related Publications
The present study aimed to investigate the mechanism and the possible approaches of solving drug resistance by silencing hypoxia-inducible factor-1 alpha of human pancreatic cancer cell line Patu8988/5-Fu cultured in hypoxia. The effective jamming fragment screened by RT-PCR for silencing HIF-1α gene was transfected into pancreatic cancer cells Patu8988/5-Fu through lentivirus. RT-PCR results showed that the effective jamming fragments for HIF-1α in lentivirus transfection was Wtl-mus-1202(C546). Combined MTT with JC-1 fluorescence staining flow cytometric analysis, the concentration of 200 μmol/L CoCl2 for 8 h was chosen to mimic hypoxia cell environment. The drug resistance significantly enhanced in response to hypoxia in Patu8988/5-Fu (p<0.05), and silence HIF-1α could reverse the multidrug resistance (P<0.05). In the Patu8988/5-Fu cells, HIF-1α and MDR1 significantly increased in response to hypoxia (p<0.05). The inhibition of HIF-1α expression synergistically downregulated the expression of the MDR1 gene in Patu8988/5-Fu cells (p<0.05). HIF-1α expression was positively correlated with the MDR1 expression (p<0.05). The upregulation of the HIF-1α and MDR1 gene expression caused by hypoxia was related with the generation of multi-drug resistance of Patu8988/5-Fu, targeted silencing HIF-1α may be a kind of way to reverse the chemotherapy drug resistance.

Chen WM, Huang MD, Kong R, et al.
Antisense Long Noncoding RNA HIF1A-AS2 Is Upregulated in Gastric Cancer and Associated with Poor Prognosis.
Dig Dis Sci. 2015; 60(6):1655-62 [PubMed] Related Publications
BACKGROUND: Long noncoding RNAs (lncRNAs) have been recently shown to play important regulatory roles in fundamental biological processes, and many of them are deregulated in several human cancers. LncRNA hypoxia-inducible factor 1alpha antisense RNA-2 (HIF1A-AS2) is overexpressed in nonpapillary clear-cell renal carcinomas and involved in cancer progression.
AIM: This study was to evaluate the expression of HIF1A-AS2 in gastric cancer (GC) and further explore its biological function in GC cells.
MATERIALS AND METHODS: Quantitative real-time polymerase chain reaction was used to detect the expression level of HIF1A-AS2 in GC tissues. The correlation of its expression with clinicopathological features was analyzed. Area under receiver operating characteristic curve (ROC(AUC)) was constructed to evaluate the diagnostic value of HIF1A-AS2. Besides, tumor cell proliferation was assessed following knockdown of HIF1A-AS2, by MTT and colony formation assay in vitro, and tumor formation assay in a nude mouse model in vivo.
RESULTS: The expression of HIF1A-AS2 was upregulated in GC tumorous tissues compared with the adjacent normal tissues (P < 0.001). Its overexpression was correlated with TNM stages (P = 0.008), tumor invasion (P = 0.016), lymph node metastasis (P = 0.042), and poor prognosis (P = 0.001). In addition, ROC(AUC) of HIF1A-AS2 was up to 0.673 (95 % CI 0.596-0.744, P < 0.001). Moreover, knockdown of HIF1A-AS2 expression by siRNA could inhibit cell proliferation in vitro and tumorigenesis in vivo.
CONCLUSIONS: HIF1A-AS2 is overexpressed in GC and may play a pivotal role in tumor cell proliferation. It can be used as a potential diagnostic and prognostic biomarker for GC.

Li G, Shan C, Liu L, et al.
Tanshinone IIA inhibits HIF-1α and VEGF expression in breast cancer cells via mTOR/p70S6K/RPS6/4E-BP1 signaling pathway.
PLoS One. 2015; 10(2):e0117440 [PubMed] Article available free on PMC after 01/12/2015 Related Publications
Hypoxia-inducible factor 1α (HIF-1α) and vascular endothelial growth factor (VEGF) play important roles in angiogenesis and tumor growth. Tanshinone IIA (T2A) is a novel antiangiogenic agent with promising antitumor effects; however, the molecular mechanism underlying the antiangiogenic effects of T2A remains unclear. In the present study, we provided evidence showing that T2A inhibited angiogenesis and breast cancer growth by down-regulating VEGF expression. Specifically, T2A repressed HIF-1α expression at the translational level and inhibited the transcriptional activity of HIF-1α, which led to the down-regulation of VEGF expression. Suppression of HIF-1α synthesis by T2A correlated with strong dephosphorylation of mammalian target of rapamycin (mTOR) and its effectors ribosomal protein S6 kinase (p70S6K) and eukaryotic initiation factor 4E-binding protein-1 (4E-BP1), a pathway regulating HIF-1α expression at the translational level. In addition, we also found that T2A inhibited the angiogenesis and growth of human breast cancer xenografts in nude mice through suppression of HIF-1α and VEGF. Our study provides novel perspectives and potential targets for the treatment of human breast cancer.

Niu F, Li Y, Lai FF, et al.
LB-1 Exerts Antitumor Activity in Pancreatic Cancer by Inhibiting HIF-1α and Stat3 Signaling.
J Cell Physiol. 2015; 230(9):2212-23 [PubMed] Related Publications
Hypoxia is widely present in pancreatic cancer and subsequently causes the overexpression of hypoxia-inducible factor-1α (HIF-1α) and signal transducer and activator of transcription-3 (Stat3). HIF-1α and Stat3 function cooperatively to regulate a number of downstream genes that are implicated in tumorigenesis. Thus, inhibition of HIF-1α and Stat3 is a potential therapeutic strategy for pancreatic cancer. In this study, we explored how LB-1, a novel triptolide (LA) derivative, exerted its antitumor effect through blockade of HIF-1α and Stat3 signaling. Our data showed that LB-1 was able to inhibit the proliferation and colony formation of Mia-PaCa2 and SW1990 cells. LB-1 suppressed HIF-1α protein accumulation by promoting its proteasome degradation and reducing transactivation. Moreover, the silence of HIF-1α by shRNA partially prevented the proliferation inhibition triggered by LB-1. As expected, LB-1 also decreased Stat3 protein accumulation and blocked the physical interactions between HIF-1α/p300/phosphor-Stat3 (p-Stat3) at the pharmacological concentration to reduce VEGF expression, thereby hypoxia-induced angiogenesis. In the Mia-PaCa2 nude xenograft model, therapeutic treatment with LB-1 significantly inhibited tumor growth and had minimal systemic toxicity compared to the mother drug LA. Furthermore, in accordance with in vitro results, HIF-1α activation and Stat3 expression in tumors were blocked by LB-1 through mTOR-dependent pathway. Taken together, these results illustrate that, as a potent inhibitor of HIF-1α and Stat3 signaling, LB-1 exhibits antitumor effect and could be potentially used to treat pancreatic cancer.

Rellinger EJ, Romain C, Choi S, et al.
Silencing gastrin-releasing peptide receptor suppresses key regulators of aerobic glycolysis in neuroblastoma cells.
Pediatr Blood Cancer. 2015; 62(4):581-6 [PubMed] Article available free on PMC after 01/04/2016 Related Publications
BACKGROUND: Under normoxic conditions, cancer cells use aerobic glycolysis as opposed to glucose oxidation for energy production; this altered metabolism correlates with poor outcomes in neuroblastoma. Hypoxia-inducible factor-1 alpha (HIF-1α) and pyruvate dehydrogenase kinase 4 (PDK4) regulate aerobic glycolysis, while pyruvate dehydrogenase phosphatase 2 (PDP2) promotes glucose oxidation. Here, we sought to determine whether gastrin-releasing peptide receptor (GRP-R) signaling regulates glucose metabolism.
PROCEDURE: Neuroblastoma cell lines, BE(2)-C and SK-N-AS, were used. PCR microararay for glucose metabolism was performed on GRP-R silenced cells. Target protein expression was validated using Western blotting and VEGF ELISA. Cobalt chloride (CoCl2 ) was used to induce chemical hypoxia. Efficacy of targeting PDK regulation in neuroblastoma was assessed using dichloroacetate (DCA) by conducting cell viability assays and Western blotting for apoptotic markers.
RESULTS: Silencing GRP-R decreased HIF-1α expression and blocked VEGF expression and secretion in both normoxic and CoCl2 induced hypoxia. PCR array analysis identified that GRP-R silencing reduced PDK4 and increased PDP2 mRNA expression. These findings were validated by Western blotting. CoCl2 induced hypoxia increased VEGF secretion, HIF-1α, and PDK4 expression. PDK4 silencing decreased HIF-1α expression and VEGF expression and secretion. DCA treatment decreased BE(2)-C and SK-N-AS proliferation while promoting cell death. GRP-R silencing and DCA treatment synergistically halted BE(2)-C proliferation.
CONCLUSIONS: We report that GRP-R regulates glucose metabolism in neuroblastoma by modulating HIF-1α, PDK4 and PDP2. PDK4 regulates glucose metabolism, in part, via regulation of HIF-1α. Synergistic consequences of GRP-R inhibition and DCA treatment may suggest a novel therapeutic strategy for the treatment of aggressive neuroblastoma.

Nozawa-Suzuki N, Nagasawa H, Ohnishi K, Morishige K
The inhibitory effect of hypoxic cytotoxin on the expansion of cancer stem cells in ovarian cancer.
Biochem Biophys Res Commun. 2015; 457(4):706-11 [PubMed] Related Publications
While an increase in progression free survival time is seen when an angiogenesis inhibitor is used in the treatment of high-relapse rate ovarian cancer, it has little effect on overall survival. A possible cause of treatment-resistance to angiogenesis inhibitors is the growth of stem cells in a hypoxic microenvironment built inside the tumor tissue by angiogenesis inhibition. In this study, we examined the possible suppression of stem cell and cancer stem cell (CSC) expansion by hypoxic cytotoxin, TX-402. TX-402, an analogue of tirapazamine, has been developed as a hypoxia selective prodrug with inhibitory effects of HIF-1 and angiogenesis. We considered TX-402 as a possible molecular-target drug candidate for ovarian cancer due to its inhibition of CSC expansion. In this study, we found that the expressions of HIF-1α and HIF-2α were increased under hypoxia in serous ovarian cancer cell lines. The expressions of HIF-1α and HIF-2α induced under hypoxia were repressed by TX-402 in a dose-dependent manner. Next, we investigated the effects of hypoxia on the expression levels of stem cell factors, Oct4, Nanog, Sox2 and Lin28, and showed that their expressions were induced by hypoxia. It was also observed that the expressions of putative ovarian cancer stem cell markers, CD133 and CD44 were induced under hypoxia. Furthermore, TX-402 was found to dose-dependently inhibit the expressions of CSC markers and stem cell factors. Oct4 expression was repressed by HIF-2α silencing, but not by HIF-1α silencing, indicating that TX-402 may repress the expression of Oct4 by inhibiting HIF-2α. We constructed CaOV3 spheroids as a 3-dimensional hypoxia model, in which the internal hypoxic region contained CSC-like cells expressing Oct4. The internal hypoxic region, which contained Oct4 expressing cells, disappeared following TX-402 treatment. In conclusion, hypoxia promoted the expansion of CSCs expressing CD133 and CD44 accompanied by an increase of stem cell factors. Its inhibition of hypoxia-induced CSC expansion makes TX-402 promising agent usable in combination for ovarian cancer therapy.

Yang B, Yang E, Liao H, et al.
ARNT2 is downregulated and serves as a potential tumor suppressor gene in non-small cell lung cancer.
Tumour Biol. 2015; 36(3):2111-9 [PubMed] Related Publications
The present study aims to investigate the expression pattern of aryl hydrocarbon receptor nuclear translocator 2 (ARNT2) protein and its clinical significance in human non-small cell lung cancer (NSCLC). We investigated the expression levels of ARNT2 in 104 NSCLC surgical specimens by immunohistochemistry and then analyzed its clinical significance. Additionally, the role of ARNT2 on the biological properties of the NSCLC line HCC827 was experimentally tested in vitro and in vivo to confirm the clinical observations. We found that the expression level of ARNT2 was significantly higher in normal lung tissues compared with NSCLC tissues (P < 0.01). Overall survival (OS) of patients with a high intratumoral ARNT2 level was significantly longer than survival of those with a low ARNT2 level (P = 0.004). In addition, intratumoral ARNT2 expression was an independent prognostic factors for OS (hazard ratio [HR] = 0.529; P = 0.001). 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay showed that the ARNT2 overexpression inhibited cell viability, while ARNT2 knockdown promoted cell growth in NSCLC cell lines HCC827 and A549. Annexin V/PI assay showed that ARNT2 overexpression increased cell apoptosis, while ARNT2 knockdown decreased cell apoptosis in HCC827 and A549 cells. Moreover, in vivo study showed that attenuated ARNT2 expression in HCC827 cells greatly promoted tumor growth, while overexpressed ARNT2 remarkably inhibited tumor growth in a HCC827 xenograft model. Taken together, our data demonstrate that ARNT2 might serve as a tumor suppressor in NSCLC progression.

Chen WH, Lecaros RL, Tseng YC, et al.
Nanoparticle delivery of HIF1α siRNA combined with photodynamic therapy as a potential treatment strategy for head-and-neck cancer.
Cancer Lett. 2015; 359(1):65-74 [PubMed] Related Publications
Combination therapy has become a major strategy in cancer treatment. We used anisamide-targeted lipid-calcium-phosphate (LCP) nanoparticles to efficiently deliver HIF1α siRNA to the cytoplasm of sigma receptor-expressing SCC4 and SAS cells that were also subjected to photodynamic therapy (PDT). HIF1α siRNA nanoparticles effectively reduced HIF1α expression, increased cell death, and significantly inhibited cell growth following photosan-mediated photodynamic therapy in cultured cells. Intravenous injection of the same nanoparticles into human SCC4 or SAS xenografted mice likewise resulted in concentrated siRNA accumulation and reduced HIF1α expression in tumor tissues. When combined with photodynamic therapy, HIF1α siRNA nanoparticles enhanced the regression in tumor size resulting in a ~40% decrease in volume after 10 days. Combination therapy was found to be substantially more effective than either HIF1α siRNA or photodynamic therapy alone. Results from caspase-3, TUNEL, and CD31 marker studies support this conclusion. Our results show the potential use of LCP nanoparticles for efficient delivery of HIF1α siRNA into tumors as part of combination therapy along with PDT in the treatment of oral squamous cell carcinoma.

Womeldorff M, Gillespie D, Jensen RL
Hypoxia-inducible factor-1 and associated upstream and downstream proteins in the pathophysiology and management of glioblastoma.
Neurosurg Focus. 2014; 37(6):E8 [PubMed] Related Publications
Glioblastoma multiforme (GBM) is a highly aggressive brain tumor with an exceptionally poor patient outcome despite aggressive therapy including surgery, radiation, and chemotherapy. This aggressive phenotype may be associated with intratumoral hypoxia, which probably plays a key role in GBM tumor growth, development, and angiogenesis. A key regulator of cellular response to hypoxia is the protein hypoxia-inducible factor–1 (HIF-1). An examination of upstream hypoxic and nonhypoxic regulation of HIF-1 as well as a review of the downstream HIF-1– regulated proteins may provide further insight into the role of this transcription factor in GBM pathophysiology. Recent insights into upstream regulators that intimately interact with HIF-1 could provide potential therapeutic targets for treatment of this tumor. The same is potentially true for HIF-1–mediated pathways of glycolysis-, angiogenesis-, and invasion-promoting proteins. Thus, an understanding of the relationship between HIF-1, its upstream protein regulators, and its downstream transcribed genes in GBM pathogenesis could provide future treatment options for the care of patients with these tumors.

Amelio I, Inoue S, Markert EK, et al.
TAp73 opposes tumor angiogenesis by promoting hypoxia-inducible factor 1α degradation.
Proc Natl Acad Sci U S A. 2015; 112(1):226-31 [PubMed] Article available free on PMC after 01/04/2016 Related Publications
Tumor hypoxia and hypoxia-inducible factor 1 (HIF-1) activation are associated with cancer progression. Here, we demonstrate that the transcription factor TAp73 opposes HIF-1 activity through a nontranscriptional mechanism, thus affecting tumor angiogenesis. TAp73-deficient mice have an increased incidence of spontaneous and chemically induced tumors that also display enhanced vascularization. Mechanistically, TAp73 interacts with the regulatory subunit (α) of HIF-1 and recruits mouse double minute 2 homolog into the protein complex, thus promoting HIF-1α polyubiquitination and consequent proteasomal degradation in an oxygen-independent manner. In human lung cancer datasets, TAp73 strongly predicts good patient prognosis, and its expression is associated with low HIF-1 activation and angiogenesis. Our findings, supported by in vivo and clinical evidence, demonstrate a mechanism for oxygen-independent HIF-1 regulation, which has important implications for individualizing therapies in patients with cancer.

Stantic M, Sakil HA, Zirath H, et al.
TAp73 suppresses tumor angiogenesis through repression of proangiogenic cytokines and HIF-1α activity.
Proc Natl Acad Sci U S A. 2015; 112(1):220-5 [PubMed] Article available free on PMC after 01/04/2016 Related Publications
The p53-family member TAp73 is known to function as a tumor suppressor and regulates genomic integrity, cellular proliferation, and apoptosis; however, its role in tumor angiogenesis is poorly understood. Here we demonstrate that TAp73 regulates tumor angiogenesis through repression of proangiogenic and proinflammatory cytokines. Importantly, loss of TAp73 results in highly vascularized tumors, as well as an increase in vessel permeability resulting from disruption of vascular endothelial-cadherin junctions between endothelial cells. In contrast, loss of the oncogenic p73 isoform ΔNp73 leads to reduced blood vessel formation in tumors. Furthermore, we show that up-regulated ΔNp73 levels are associated with increased angiogenesis in human breast cancer and that inhibition of TAp73 results in an accumulation of HIF-1α and up-regulation of HIF-1α target genes. Taken together, our data demonstrate that loss of TAp73 or ΔNp73 up-regulation activates the angiogenic switch that stimulates tumor growth and progression.

Feng C, Ding G, Jiang H, et al.
Loss of MLH1 confers resistance to PI3Kβ inhibitors in renal clear cell carcinoma with SETD2 mutation.
Tumour Biol. 2015; 36(5):3457-64 [PubMed] Related Publications
Renal clear cell carcinoma (ccRCC) is characterized by frequent mutation in SETD2, which has recently been shown to regulate mismatch repair (MMR). We aim to investigate the association between MMR machinery genes and SETD2 mutation in ccRCC. We exploited the Genomics of Drug Sensitivity in Cancer (GDSC) database to identify selective inhibitors for SETD2 mutant ccRCC cells. We also exploited the Cancer Genome Atlas (TCGA) database to study the association between SETD2 status and MMR-related genes. In vitro studies were performed to validate the in silico findings. Reproduction of the GDSC database revealed four compounds with significant selectivity for SETD2 mutant ccRCC cells, amongst which two compounds targeted PI3Kβ. Phosphorylation of AKT at both S473 and T308 was decreased following PI3Kβ inhibitor treatment in SETD2 mutant ccRCC cells, whereas the basal pAKT level was not changed between mutant and wild-type SETD2. Both decreased MLH1 and increased AKT levels induced lower PMS2, indicating that MMR was mediated by SETD2 via both AKT and MLH1 in ccRCC. Analysis of the TCGA database further revealed high tendency of homozygous co-deletion of SETD2 and MLH1. In the absence of MLH1, suppression of pAKT by PI3Kβ inhibitor was mitigated and inhibition in cell proliferation, invasiveness, migratory ability and tumourigenesis was partially restored. Besides the reported H3K36-trimethylation pathway, we found that SETD2 mutation also mediated MMR via AKT-induced PMS2 decrease and co-loss of MLH1 loss in ccRCC.

Han S, Huh J, Kim W, et al.
Phospholipase D activates HIF-1-VEGF pathway via phosphatidic acid.
Exp Mol Med. 2014; 46:e126 [PubMed] Article available free on PMC after 01/04/2016 Related Publications
Growth factor-stimulated phospholipase D (PLD) catalyzes the hydrolysis of phosphatidylcholine (PC), generating phosphatidic acid (PA) which may act as a second messenger during cell proliferation and survival. Therefore, PLD is believed to play an important role in tumorigenesis. In this study, a potential mechanism for PLD-mediated tumorigenesis was explored. Ectopic expression of PLD1 or PLD2 in human glioma U87 cells increased the expression of hypoxia-inducible factor-1α (HIF-1α) protein. PLD-induced HIF-1 activation led to the secretion of vascular endothelial growth factor (VEGF), a HIF-1 target gene involved in tumorigenesis. PLD induction of HIF-1α was significantly attenuated by 1-butanol which blocks PA production by PLD, and PA per se was able to elevate HIF-1α protein level. Inhibition of mTOR, a PA-responsive kinase, reduced the levels of HIF-1α and VEGF in PLD-overexpressed cells. Epidermal growth factor activated PLD and increased the levels of HIF-1α and VEGF in U87 cells. A specific PLD inhibitor abolished expression of HIF-1α and secretion of VEGF. PLD may utilize HIF-1-VEGF pathway for PLD-mediated tumor cell proliferation and survival.

Sharma S, Kapahi R, Sambyal V, et al.
No association of hypoxia inducible factor-1α gene polymorphisms with breast cancer in North-West Indians.
Asian Pac J Cancer Prev. 2014; 15(22):9973-8 [PubMed] Related Publications
BACKGROUND: Hypoxia inducible factor-1 alpha (HIF-1α) is the key regulator of cellular responses to hypoxia and plays a central role in tumour growth. Presence of Single nucleotide polymorphisms (SNPs) in the critical regulatory domains of HIF-1α may result in the overexpression of the protein and subsequent changes in the expression of the downstream target genes. The aim of study was to investigate the association of three SNPs (g.C111A, g.C1772T and g.G1790A) of HIF-1α with the risk of breast cancer in North Indian sporadic breast cancer patients.
MATERIALS AND METHODS: A total of 400 subjects, including 200 healthy controls and 200 patients with breast cancer were recruited in this study. Genotypes were determined using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method.
RESULTS: The CC and CA genotype frequency of HIF-1α g.C111A polymorphism was 100 vs 99% and 0 vs 1% in breast cancer patients and healthy controls respectively. The frequencies of CC, CT and TT genotype of g.C1772T polymorphism were 76 vs 74.5%, 19 vs 21% and 5 vs 4.5% in breast cancer patients and control individuals respectively. There was no significant difference in genotype and allele frequencies of HIF-1α g.C1772T polymorphism between cases and control individuals (p>0.05). For g.G1790A genotypes, all patients and controls had only GG genotype.
CONCLUSIONS: The three HIF-1α polymorphisms (g.C111A, g.C1772T and g.G1790A) are not associated with breast cancer risk in North-West Indian patients.

Hu H, Wang Z, Liu Y, et al.
Genome-wide transcriptional analyses of Chinese patients reveal cell migration is attenuated in IDH1-mutant glioblastomas.
Cancer Lett. 2015; 357(2):566-74 [PubMed] Related Publications
Patients with isocitrate dehydrogenase 1 (IDH1)-mutant glioblastoma exhibit increased survival compared with those with wild-type IDH1 tumors. The magnitude of this finding has led to the use of IDH1 mutations as diagnostic and prognostic biomarkers. However, the mechanisms underlying the reported correlation between the IDH1 mutation and increased survival have not been fully revealed. In this work, based on genome-wide transcriptional analyses of 69 Chinese patients with glioblastoma, we have found that the focal adhesion pathway is significantly downregulated in IDH1-mutant glioblastomas. The impaired focal adhesion leads to compromised cell migration and tumor invasion, contributing to the optimistic prognosis of these patients. Moreover, the signature genes of HIF-1α, the downstream factor of mutated IDH1, are found to be suppressed in IDH1-mutant gliomas. Given the role of HIF-1α in cell migration, we conclude that the attenuation of HIF-1α-dependent glioblastoma cell infiltration contributes to the better outcomes of patients with IDH1-mutant gliomas.

Meka PB, Cingeetham A, Nanchari SR, et al.
HIF-1α (1772C>T) polymorphism as marker for breast cancer development.
Tumour Biol. 2015; 36(5):3215-20 [PubMed] Related Publications
Hypoxia-inducible factor 1α (HIF-1α) is an important transcription factor that regulates different cellular responses to hypoxia. HIF-1α is rapidly degraded by von Hippel-Lindau (VHL) protein under normoxic conditions and stabilized under hypoxia. A common variant of HIF-1α (1772C>T) (rs 11549465) polymorphism, corresponding to an amino acid change from proline to serine at 582 position within the oxygen-dependent degradation domain, results in increased stability of the protein and altered transactivation of its target genes. The present study was aimed to find the association between HIF-1α (1772C>T) (rs 11549465) polymorphism and breast cancer development. For this purpose, 348 primary breast cancer patients and 320 healthy and age-matched controls were genotyped through PCR-RFLP method. The genotype frequencies were compared between patients and controls, and their influence on clinical characteristics of breast cancer patients was analyzed. Our study revealed a significant increase of TT genotype in breast cancer patients compared to controls (p = 0.038). Further, TT genotype and T allele were found to be associated with progesterone receptor (PR)-negative status (p < 0.09). None of the clinical variables revealed significant association with HIF-1α (1772C>T) (rs 11549465) polymorphism.

Jóźwiak P, Krześlak A, Bryś M, Lipińska A
Glucose-dependent glucose transporter 1 expression and its impact on viability of thyroid cancer cells.
Oncol Rep. 2015; 33(2):913-20 [PubMed] Related Publications
Cancer cells exhibit an altered metabolism characterized by enhanced glycolysis and glucose consumption. In glucose‑addicted cancer cells upregulation of glucose transport across the plasma membrane is mediated by a family of facilitated glucose transporter proteins, particularly glucose transporter 1 (GLUT1). The aim of the present study was to investigate the impact of GLUT1 expression on glucose uptake and viability of FTC-133 and 8305c thyroid cancer cells growing in hypoglycemic, normoglycemic and hyperglycemic conditions. The results showed that the total expression of GLUT1 was higher in the two cell types growing in low glucose compared to cells growing in normoglycemia or hyperglycemia and this was correlated with AKT Ser473 phosphorylation but not with the expression of hypoxia inducible factor α (HIF1α). However, the membrane expression of GLUT1 was correlated with HIF1α expression. HIF1α expression was positively correlated with the glucose concentration in FTC-133 cells, whereas this expression was inversely correlated in 8305c cells. Glucose uptake was dependent on the membrane level of GLUT1 but not total GLUT1 expression. Downregulation of GLUT1 expression by RNAi in FTC-133 cells caused a reduction in glucose uptake but did not significantly affect cell viability. In the case of 8305c cells showing low endogenous GLUT1 expression and lack of HIF1α expression in normoxic conditions GLUT1 RNAi impacted cell viability. These data suggested that GLUT1 may be part of an AKT1-dependent mechanism allowing cells to survive in low levels of glucose. Glucose concentration inversely affected HIF1α expression and the level of GLUT1 in membrane as well as glucose uptake in FTC-133 and 8305c cells. The extent of GLUT1 impact on cell viability was also cell-type-dependent.

Lei J, Fan L, Wei G, et al.
Gli-1 is crucial for hypoxia-induced epithelial-mesenchymal transition and invasion of breast cancer.
Tumour Biol. 2015; 36(4):3119-26 [PubMed] Related Publications
Hypoxia can induce HIF-1α expression and promote the epithelial-mesenchymal transition (EMT) and invasion of cancer cells. However, their mechanisms remain unclear. The objective of this study was to evaluate the role of Gli-1, an effector of the Hedgehog pathway, in the hypoxia-induced EMT and invasion of breast cancer cells. Human breast cancer MDA-MB-231 cells were transfected with HIF-1α or Gli-1-specific small interfering RNA (siRNA) and cultured under a normoxic or hypoxic condition. The relative levels of HIF-1α, Gli-1, E-cadherin, and vimentin in the cells were characterized by quantitative RT-PCR and Western blot assays, and the invasion of MDA-MB-231 cells was determined. Data was analyzed by Student T test, one-way ANOVA, and post hoc LSD test or Mann-Whitney U when applicable. We observed that hypoxia significantly upregulated the relative levels of vimentin expression, but downregulated E-cadherin expression and promoted the invasion of MDA-MB-231 cells, associated with upregulated HIF-1α translation and Gil-1 expression. Knockdown of HIF-1α mitigated hypoxia-modulated Gil-1, vimentin and E-cadherin expression, and invasion of MDA-MB-231 cells. Knockdown of Gil-1 did not significantly change hypoxia-upregulated HIF-1α translation but completely eliminated hypoxia-modulated vimentin and E-cadherin expression and invasion of MDA-MB-231 cells. These data indicate that Gil-1 is crucial for hypoxia-induced EMT and invasion of breast cancer cells and may be a therapeutic target for intervention of breast cancer metastasis.

Gao H, Xie J, Peng J, et al.
Hispidulin inhibits proliferation and enhances chemosensitivity of gallbladder cancer cells by targeting HIF-1α.
Exp Cell Res. 2015; 332(2):236-46 [PubMed] Related Publications
Gallbladder cancer (GBC) is an aggressive malignancy of the bile duct, which is associated with a low (5-year) survival and poor prognosis. The transcription factor HIF-1α is implicated in the angiogenesis, cell survival, epithelial mesenchymal transition (EMT) and invasiveness of GBC. In this study, we have investigated the role of HIF-1α in the pathobilogy of GBC and effect of hispidulin on the molecular events controlled by this transcription factor. We observed that hispidulin caused induction of apoptosis, blockade of growth and cell cycle progression in GBC cells. Our results have demonstrated for the first time that hispidulin-exerted anti-tumor effect involved the suppression of HIF-1α signaling. Hispidulin was found to repress the expression of HIF-1α protein dose-dependently without affecting the HIF-1α mRNA expression. In addition, the inhibition of HIF-1α protein synthesis was revealed to be mediated through the activation of AMPK signaling. Hispidulin also sensitized the tumor cells to Gemcitabine and 5-Fluoroucil by down-regulating HIF-1α/P-gp signaling. Given the low cost and exceedingly safe profile, hispidulin appears to be a promising and novel chemosensitizer for GBC treatment.

Nagaraju GP, Zhu S, Ko JE, et al.
Antiangiogenic effects of a novel synthetic curcumin analogue in pancreatic cancer.
Cancer Lett. 2015; 357(2):557-65 [PubMed] Related Publications
Hypoxia-inducible factors (HIFs) and NF-κB play essential roles in cancer cell growth and metastasis by promoting angiogenesis. Heat shock protein 90 (Hsp90) serves as a regulator of HIF-1α and NF-κB protein. We hypothesized that curcumin and its analogues EF31 and UBS109 would disrupt angiogenesis in pancreatic cancer (PC) through modulation of HIF-1α and NF-κB. Conditioned medium from MIA PaCa-2 or PANC-1 cells exposed to curcumin and its analogues in vitro significantly impaired angiogenesis in an egg CAM assay and blocked HUVEC tube assembly in comparison to untreated cell medium. In vivo, EF31 and UBS109 blocked the vascularization of subcutaneous matrigel plugs developed by MIA PaCa-2 in mice. Significant inhibition of VEGF, angiopoietin 1, angiopoietin 2, platelet derived growth factor, COX-2, and TGFβ secretion was observed in PC cell lines treated with UBS109, EF31 or curcumin. Treatment with UBS109, EF31 or curcumin inhibited HSP90, NF-κB, and HIF-1α transcription in PC cell lines. UBS109 and EF31 inhibited HSP90 and HIF-1α expression even when elevated due to NF-κB (p65) overexpression. Finally, we demonstrate for the first time that curcumin analogues EF31 and UBS109 induce the downregulation of HIF-1α, Hsp90, COX-2 and VEGF in tumor samples from xenograft models compared to untreated xenografts. Altogether, these results suggest that UBS109 and EF31 are potent curcumin analogues with antiangiogenic activities.

Yan Q, Chen P, Wang S, et al.
Association between HIF-1α C1772T/G1790A polymorphisms and cancer susceptibility: an updated systematic review and meta-analysis based on 40 case-control studies.
BMC Cancer. 2014; 14:950 [PubMed] Article available free on PMC after 01/04/2016 Related Publications
BACKGROUND: HIF-1 (hypoxia-inducible factor 1) is a transcriptional activator that functions as a critical regulator of oxygen homeostasis. Recently, a large number of epidemiological studies have investigated the relationship between HIF-1α C1772T/G1790A polymorphisms and cancer susceptibility. However, the results remain inconclusive. Therefore, we performed a meta-analysis on all of the available case-control studies to systematically summarize the possible association.
METHODS: A literature search was performed using PubMed and the Web of Science database to obtain relevant published studies. Pooled odds ratios (ORs) and corresponding 95% confidence intervals (CIs) for the relationship between HIF-1α C1772T/G1790A polymorphisms and cancer susceptibility were calculated using fixed- and random-effects models when appropriate. Heterogeneity tests, sensitivity analyses and publication bias assessments were also performed in our meta-analysis.
RESULTS: A total of 40 studies met the inclusion criteria were included in the meta-analysis: 40 studies comprised of 10869 cases and 14289 controls for the HIF-1α C1772T polymorphism and 30 studies comprised of 7117 cases and 10442 controls for the HIF-1α G1790A polymorphism. The results demonstrated that there were significant association between the HIF-1α C1772T polymorphism and cancer susceptibility under four genetic models (TT vs. CC: OR = 1.63, 95% CI = 1.02-2.60; CT + TT vs. CC: OR = 1.15, 95% CI = 1.01-1.34; TT vs. CT + CC: OR = 2.11, 95% CI = 1.32-3.77; T vs. C: OR = 1.21, 95% CI = 1.04-1.41). Similarly, the statistically significant association between the HIF-1α G1790A polymorphism and cancer susceptibility was found to be consistently strong in all of the genetic models. Moreover, increased cancer risk was observed when the data were stratified by cancer type, ethnicity and the source of controls.
CONCLUSIONS: This meta-analysis demonstrates that both the C1772T and G1790A polymorphisms in the HIF-1α gene likely contribute to increased cancer susceptibility, especially in the Asian population and in breast cancer, lung cancer, pancreatic cancer and oral cancer. However, further research is necessary to evaluate the relationship between these polymorphisms and cancer risk.

Wang YF, Ma SR, Wang WM, et al.
Inhibition of survivin reduces HIF-1α, TGF-β1 and TFE3 in salivary adenoid cystic carcinoma.
PLoS One. 2014; 9(12):e114051 [PubMed] Article available free on PMC after 01/04/2016 Related Publications
In the present study, we explored the expression and correlation of survivin with HIF-1α, TGF-β1 and TFE3 in adenoid cystic carcinoma (AdCC). The expression of survivin, HIF-1α, TGF-β1 and TFE3 was assessed by immunohistochemical staining of a tissue microarray containing tissue samples of normal salivary gland (NSG), pleomorphic adenoma (PA) and AdCC. Correlation analysis of these proteins revealed that increased survivin expression was associated with the overexpression of HIF-1α (P<0.001, r = 0.5599), TGF-β1 (P<0.001, r = 0.6616) and TFE3 (P<0.001, r = 0.7747). The expression of survivin, HIF-1α, TGF-β1 and TFE3 was not correlated with the pathological type of human AdCC (P>0.05). Selective inhibition of survivin by YM155 and siRNA significantly reduced human SACC-83 cell proliferation, with the corresponding decrease in expression of HIF-1α, TGF-β1 and TFE3. The data indicate that the overexpression of survivin in AdCC is related to HIF-1α, TGF-β1 and TFE3. We hypothesize from these findings that the inhibition of survivin may be a novel strategy for neoadjuvant chemotherapeutic and radiosensitive treatment of AdCC.

Disclaimer: This site is for educational purposes only; it can not be used in diagnosis or treatment.

Cite this page: Cotterill SJ. SETD2, Cancer Genetics Web: http://www.cancer-genetics.org/SETD2.htm Accessed:

Creative Commons License
This page in Cancer Genetics Web by Simon Cotterill is licensed under a Creative Commons Attribution-ShareAlike 4.0 International License.
Note: content of abstracts copyright of respective publishers - seek permission where appropriate.

 [Home]    Page last revised: 17 August, 2015     Cancer Genetics Web, Established 1999