Prognostic Potential of DNA Methylation and Transcript Levels of HIF1A and EPAS1 in Colorectal Cancer

Rawłuszko-Wieczorek, Agnieszka Anna; Horbacka, Karolina; Krokowicz, Piotr; Misztal, Matthew; Jagodzińśki, Paweł P.

doi:10.1158/1541-7786.mcr-14-0054

Cited by 51 publications

(52 citation statements)

References 44 publications

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“…Our analysis is in line with studies of other tumor types wherein HIF2α but not HIF1α is associated with decreased tumor growth and better patient outcome (24,(38)(39)(40)(41)(42). This further underscores how tumor context determines if HIF2α acts as an oncogene (e.g., ccRCC and adult glioma) (12,26,43,44) or can actually have tumor-suppressive properties (e.g., soft tissue sarcomas, hepatocellular carcinoma, and colon cancer) (24,(38)(39)(40)(41)(42). Furthermore, in nonsmall lung cancer, HIF2α has been described both as an oncogene and a tumor suppressor (45,46).…”

Section: Discussionsupporting

confidence: 89%

Combined epigenetic and differentiation-based treatment inhibits neuroblastoma tumor growth and links HIF2α to tumor suppression

Westerlund

Shi

Toskas

et al. 2017

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

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Neuroblastoma is a pediatric cancer characterized by variable outcomes ranging from spontaneous regression to life-threatening progression. High-risk neuroblastoma patients receive myeloablative chemotherapy with hematopoietic stem-cell transplant followed by adjuvant retinoid differentiation treatment. However, the overall survival remains low; hence, there is an urgent need for alternative therapeutic approaches. One feature of high-risk neuroblastoma is the high level of DNA methylation of putative tumor suppressors. Combining the reversibility of DNA methylation with the differentiation-promoting activity of retinoic acid (RA) could provide an alternative strategy to treat high-risk neuroblastoma. Here we show that treatment with the DNAdemethylating drug 5-Aza-deoxycytidine (AZA) restores high-risk neuroblastoma sensitivity to RA. Combined systemic distribution of AZA and RA impedes tumor growth and prolongs survival. Genomewide analysis of treated tumors reveals that this combined treatment rapidly induces a HIF2α-associated hypoxia-like transcriptional response followed by an increase in neuronal gene expression and a decrease in cell-cycle gene expression. A small-molecule inhibitor of HIF2α activity diminishes the tumor response to AZA+RA treatment, indicating that the increase in HIF2α levels is a key component in tumor response to AZA+RA. The link between increased HIF2α levels and inhibited tumor growth is reflected in large neuroblastoma patient datasets. Therein, high levels of HIF2α, but not HIF1α, significantly correlate with expression of neuronal differentiation genes and better prognosis but negatively correlate with key features of high-risk tumors, such as MYCN amplification. Thus, contrary to previous studies, our findings indicate an unanticipated tumor-suppressive role for HIF2α in neuroblastoma.neuroblastoma | differentiation | retinoic acid | 5-Aza-dC | HIF2a

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Section: Discussionsupporting

confidence: 89%

Combined epigenetic and differentiation-based treatment inhibits neuroblastoma tumor growth and links HIF2α to tumor suppression

Westerlund

Shi

Toskas

et al. 2017

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

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“…Indeed, further studies have to elucidate the exact roles for the different subunits precisely vis-à-vis. Regarding colorectal cancer, one study recently described HIF-2α to prevent colorectal cancer progression [53]. Taniguchi et al further reported a beneficial effect for the HIF-2 subunit when studying the impact of PHD inhibition on radiation-induced gastrointestinal toxicity [59].…”

Section: Hif and Ibdmentioning

confidence: 99%

Oxygen sensing in intestinal mucosal inflammation

Flück

Fandrey

2015

Pflugers Arch - Eur J Physiol

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Hypoxia is a hallmark of chronically inflamed tissue. Hypoxia develops from vascular dysfunction and increased oxygen consumption by infiltrating leukocytes. With respect to inflammatory bowel disease (IBD), hypoxia is likely to be of particular importance: Impairment of the intestinal barrier during IBD allows anoxia from the lumen of the gut to spread to formerly normoxic tissue. In addition, disturbed perfusion of inflamed tissue and a higher oxygen demand of infiltrating immune cells lead to low oxygen levels in inflamed mucosal tissue. Here, cells become hypoxic and must now adapt to this condition. The hypoxia inducible factor (HIF)-1 complex is a key transcription factor for cellular adaption to low oxygen tension. HIF-1 is a heterodimer formed by two subunits: HIF-α (either HIF-1α or HIF-2α) and HIF-1β. Under normoxic conditions, hydroxylation of the HIF-α subunit by specific oxygen-dependent prolyl hydroxylases (PHDs) leads to ubiquitin proteasome-dependent degradation. Under hypoxic conditions, however, PHD activity is inhibited; thus, HIF-α can translocate into the nucleus, dimerize with HIF-1β, and bind to hypoxia-responsive elements of HIF-1 target genes. So far, most studies have addressed the function of HIF-1α in intestinal epithelial cells and the effect of HIF stabilization by PHD inhibitors in murine models of colitis. Furthermore, the role of HIF-1α in immune cells becomes more and more important as T cells or dendritic cells for which HIF-1 is of critical importance are highly involved in the pathogenesis of IBD. This review will summarize the function of HIF-1α and the therapeutic prospects for targeting the HIF pathway in intestinal mucosal inflammation.

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“…Genes regulated by EPAS1 are enriched in biological processes including signaling, cell communications, and system development because EPAS1 downstream genes are significantly enriched in hypoxia responsive gene [6]. EPAS1 gene expression is reduced in many diseases [7,8].…”

Section: Introductionmentioning

confidence: 99%

TLR4 Overexpression Inhibits Endothelial PAS Domain-Containing Protein 1 Expression in the Lower Respiratory Tract of Patients with Chronic COPD

Li²,

Ning³

2016

Cell Physiol Biochem

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Background/Aims: The study was designed to explore the potential relationship of TLR4 and endothelial PAS domain-containing protein 1 (EPAS1) in vivo and vitro experiments. Methods: Bronchoalveolar lavage fluid (BALF) samples were collected from 55 chronic obstructive pulmonary disease (COPD) patients and 25 healthy subjects. The differential cell count was performed using Wright-Giemsa staining. The expression levels of TLR4 and TLR5 were detected by RT-qPCR. The levels of methylation and mRNA expression of EPAS1 were assayed by bisulfite sequencing PCR and real-time PCR. The correlation of TLR4 and EPAS1 was also analyzed in TLR 4-overexpressing endothelial cells. Results: The results showed that the number of neutrophils, lymphocytes and macrophages and expression of TLR 4 were significantly increased in lower respiratory tract of COPD patients. Moreover, decreased EPAS1 mRNA and increased EPAS1 promoter methylation were detected in COPD, which were closely associated with increased TLR4 expression. According to in vitro experiments, TLR 4 inhibited EPAS1 mRNA expression and promoted promoter methylation in endothelial cells. Conclusion: These findings suggest that TLR4 over-expression decreased EPAS1expression which contributes to the progress of COPD.

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Prognostic Potential of DNA Methylation and Transcript Levels of HIF1A and EPAS1 in Colorectal Cancer

Cited by 51 publications

References 44 publications

Combined epigenetic and differentiation-based treatment inhibits neuroblastoma tumor growth and links HIF2α to tumor suppression

Combined epigenetic and differentiation-based treatment inhibits neuroblastoma tumor growth and links HIF2α to tumor suppression

Oxygen sensing in intestinal mucosal inflammation

TLR4 Overexpression Inhibits Endothelial PAS Domain-Containing Protein 1 Expression in the Lower Respiratory Tract of Patients with Chronic COPD

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