Up-regulation of the hypoxia-inducible factor–1 transcriptional pathway in colorectal carcinomas

Furlan, Daniela; Sahnane, Nora; Carnevali, Ileana; Cerutti, Roberta; Bertoni, Francesco; Kwee, Ivo; Uccella, Silvia; Bertolini, Valentina; Chiaravalli, Anna Maria; Capella, Carlo

doi:10.1016/j.humpath.2008.02.013

Cited by 33 publications

(25 citation statements)

References 28 publications

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“…In HCT116 cells, JMJD1A is robustly induced during hypoxia in a HIF-1␣-dependent manner (Fig. 6C), consistent with a report that colorectal carcinomas have a hypoxic signature (13). JMJD1A expression is also significantly higher in renal cell carcinoma (14,45), a cancer type associated with loss of the VHL tumor suppressor and constitutive activation of HIF and its transcriptional targets (Fig.…”

Section: Resultssupporting

confidence: 89%

Regulation of the Histone Demethylase JMJD1A by Hypoxia-Inducible Factor 1α Enhances Hypoxic Gene Expression and Tumor Growth

Krieg

Rankin

Chan

et al. 2010

Molecular and Cellular Biology

315

319

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The hypoxia-inducible transcription factors (HIFs) directly and indirectly mediate cellular adaptation to reduced oxygen tensions. Recent studies have shown that the histone demethylase genes JMJD1A, JMJD2B, and JARID1B are HIF targets, suggesting that HIFs indirectly influence gene expression at the level of histone methylation under hypoxia. In this study, we identify a subset of hypoxia-inducible genes that are dependent on JMJD1A in both renal cell and colon carcinoma cell lines. JMJD1A regulates the expression of adrenomedullin (ADM) and growth and differentiation factor 15 (GDF15) under hypoxia by decreasing promoter histone methylation. In addition, we demonstrate that loss of JMJD1A is sufficient to reduce tumor growth in vivo, demonstrating that histone demethylation plays a significant role in modulating growth within the tumor microenvironment. Thus, hypoxic regulation of JMJD1A acts as a signal amplifier to facilitate hypoxic gene expression, ultimately enhancing tumor growth.Cellular hypoxia occurs when the demands of growth and metabolism of a tissue surpass the vascular oxygen supply. In response to hypoxia, cells undergo specific alterations in gene expression patterns geared to promote cell survival and maintain homeostasis. This response not only is important in normal development but also is a critical part in the progression of cancers (7). Hypoxia has been implicated in activating the metabolic shift to anaerobic glycolysis, promoting the epithelial-to-mesenchymal transition (EMT), inducing the secretion of proangiogenic factors, and remodeling the extracellular matrix. Although several transcription programs are activated in response to hypoxia, the hypoxia-inducible factors (HIFs) regulate a critical repertoire of genes, making them central regulators of the cellular response to hypoxia (10, 34).The HIFs are heterodimeric transcription factors consisting of an oxygen-sensitive alpha subunit (HIF-1␣, HIF-2␣, or HIF-3␣) and a constitutively expressed HIF-1␤ subunit (also known as the arylhydrocarbon nuclear translocator [ARNT]). Under conditions where oxygen concentration is not limiting, HIF-␣ subunits are hydroxylated by prolyl-hydroxylases, targeting them for ubiquitin-mediated degradation by the von Hippel-Lindau tumor suppressor (VHL) (18,19). Under hypoxic conditions, HIF-␣ protein is stabilized, translocates to the nucleus, dimerizes with ARNT, and binds hypoxia-responsive elements (HREs) in the regulatory regions of target genes (51). HIF-1␣ and HIF-2␣ will bind the same sequences in cells but do not have completely overlapping abilities to regulate genes (5, 17, 44). Under certain conditions, HIF-3␣ functions as a dominant negative, antagonizing the activity of HIF-1 and HIF-2 (32).Several hundred genes are induced in response to hypoxia, and a great deal of research has been focused on identifying direct HIF target genes (34). The massive transcriptional reorganization mediated by hypoxia and HIFs suggests that changes in histone modification would create epigenetic reinforcement o...

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Section: Resultssupporting

confidence: 89%

Regulation of the Histone Demethylase JMJD1A by Hypoxia-Inducible Factor 1α Enhances Hypoxic Gene Expression and Tumor Growth

Krieg

Rankin

Chan

et al. 2010

Molecular and Cellular Biology

315

319

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“…To evaluate the statistically significant difference in the ratio of cancerous EPAS1 mRNA level to histopathologically unchanged tissue EPAS1 mRNA level between the three DNA methylation ranges (0%-1% methylation, 1%-10% methylation, and 10%-100% methylation), the nonparametric Kruskal-Wallis test was used. HIF1A mRNA levels were increased in cancerous compared with noncancerous tissue (8,11,12,33,34). However, other studies reported a constant HIF1A mRNA level in tumor cells and suggested mainly posttranslational regulation of HIF1A expression (35)(36)(37), which is consistent with our observations.…”

Section: Discussionsupporting

confidence: 92%

“…The level of HIF1a and EPAS1 protein was also determined in colorectal cancer, but the results are inconclusive. HIF1a was correlated with poor patient prognosis by three independent studies, but three consecutive articles showed lack of such association in colorectal cancer (3)(4)(5)(6)(7)(8)(9). Moreover, Yoshimura and colleagues demonstrated strong positive immunohistochemical staining of EPAS1 in advanced colorectal cancer compared with low-grade tumors (6).…”

Section: Discussionmentioning

confidence: 99%

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

Rawłuszko-Wieczorek¹,

Horbacka

Krokowicz

et al. 2014

Molecular Cancer Research

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Hypoxic conditions during the formation of colorectal cancer may support the development of more aggressive tumors. Hypoxia-inducible factor (HIF) is a heterodimeric complex, composed of oxygen-induced HIFa and constitutively expressed HIFb subunits, which mediates the primary transcriptional response to hypoxic stress. Among HIFa isoforms, HIF1a (HIF1A) and endothelial PAS domain-containing protein 1 (EPAS1) are able to robustly activate hypoxia-responsive gene signatures. Although posttranslational regulation of HIFa subunits is well described, less is known about their transcriptional regulation. Here, molecular analysis determined that EPAS1 mRNA was significantly reduced in primary colonic adenocarcinoma specimens compared with histopathologically nonneoplastic tissue from 120 patients. In contrast, no difference in HIF1A mRNA levels was observed between cancerous and noncancerous tissue. Bisulfite DNA sequencing and high-resolution melting analysis identified significant DNA hypermethylation in the EPAS1 regulatory region from cancerous tissue compared with nonneoplastic tissue. Importantly, multivariate Cox regression analysis revealed a high HR for patients with cancer with low EPAS1 transcript levels (HR, 4.91; 95% confidence interval, CI, 0.42-56.15; P ¼ 0.047) and hypermethylated EPAS1 DNA (HR, 33.94; 95% CI, 2.84-405.95; P ¼ 0.0054). Treatment with a DNA methyltransferase inhibitor, 5-Aza-2 0 -deoxycytidine (5-aza-dC/Decitabine), upregulated EPAS1 expression in hypoxic colorectal cancer cells that were associated with DNA demethylation of the EPAS1 regulatory region. In summary, EPAS1 is transcriptionally regulated by DNA methylation in colorectal cancer.Implications: DNA methylation and mRNA status of EPAS1 have novel prognostic potential for colorectal cancer.

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“…Tumor hypoxia can be caused by antiangiogenic therapy (8), which then mediates resistance to antiangiogenesis (9)(10)(11). The hypoxia-mediated increase of hypoxiainducible factors (HIF) is critical to the establishment and progression of many cancers via HIF-dependent activation of genes that allow cancer cells to survive, metastasize, and develop resistance to chemotherapeutic agents (12)(13)(14)(15)(16)(17).…”

Section: Introductionmentioning

confidence: 99%

Phase I Study of the Antiangiogenic Antibody Bevacizumab and the mTOR/Hypoxia-Inducible Factor Inhibitor Temsirolimus Combined with Liposomal Doxorubicin: Tolerance and Biological Activity

Moroney

Moulder

et al. 2012

Clinical Cancer Research

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Purpose: Preclinical data suggest that combining the mTOR/hypoxia-inducible factor (HIF) inhibitor temsirolimus and the antiangiogenesis antibody bevacizumab may augment antitumor activity as well as resensitize cells to anthracyclines.Experimental Design: We initiated a phase I study of bevacizumab and temsirolimus plus liposomal doxorubicin in patients with advanced malignancies. Patients (N ¼ 136) were enrolled according to a modified 3 þ 3 design plus dose expansion in responsive tumor types.Results: The most common cancers were breast (n ¼ 29), epithelial ovarian (n ¼ 23), and colorectal cancer (n ¼ 17). The median number of prior chemotherapy regimens was four (range: 0-16). Grade 3 or higher adverse events (> 5%) included pancytopenia, mucositis, hand-foot syndrome, hypertension, and fistula. This regimen led to a 21% (n ¼ 28) stable disease (SD) ! 6 months and 21% (n ¼ 29) rate of partial or complete remission [PR/CR; (total SD ! 6 months/PR/CR ¼ 42% (n ¼ 57)]. PR/CR was most common in parotid gland adenocarcinoma (4/6, 67%), metaplastic breast cancer (5/12, 42%), endometrial endometrioid carcinoma (6/15, 40%), and in patients with a PIK3CA mutation and/or a PTEN mutation/loss (11/28, 39%). The maximum tolerated dose was liposomal doxorubicin 30 mg/m 2 and bevacizumab 15 mg/kg every three weeks with temsirolimus 25 mg weekly. Conclusions: Patients tolerated bevacizumab and temsirolimus together with liposomal doxorubicin. Further evaluation, especially in patients with parotid, metaplastic breast, and endometrial endometrioid cancer, and in patients with PIK3CA and/or PTEN aberrations is warranted.

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Up-regulation of the hypoxia-inducible factor–1 transcriptional pathway in colorectal carcinomas

Cited by 33 publications

References 28 publications

Regulation of the Histone Demethylase JMJD1A by Hypoxia-Inducible Factor 1α Enhances Hypoxic Gene Expression and Tumor Growth

Regulation of the Histone Demethylase JMJD1A by Hypoxia-Inducible Factor 1α Enhances Hypoxic Gene Expression and Tumor Growth

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

Phase I Study of the Antiangiogenic Antibody Bevacizumab and the mTOR/Hypoxia-Inducible Factor Inhibitor Temsirolimus Combined with Liposomal Doxorubicin: Tolerance and Biological Activity

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