The aryl hydrocarbon receptor repressor (AHRR) is a bHLH/Per-ARNT-Sim transcription factor located in a region of chromosome 5 (5p15.3) that has been proposed to contain one or more tumor suppressor genes. We report here consistent downregulation of AHRR mRNA in human malignant tissue from different anatomical origins, including colon, breast, lung, stomach, cervix, and ovary, and demonstrate DNA hypermethylation as the regulatory mechanism of AHRR gene silencing. Knockdown of AHRR gene expression in a human lung cancer cell line using siRNA significantly enhanced in vitro anchorage-dependent and -independent cell growth as well as cell growth after transplantation into immunocompromised mice. In addition, knockdown of AHRR in non-clonable normal human mammary epithelial cells enabled them to grow in an anchorage-independent manner. Further, downregulation of AHRR expression in the human lung cancer cell line conferred resistance to apoptotic signals and enhanced motility and invasion in vitro and angiogenic potential in vivo. Ectopic expression of AHRR in tumor cells resulted in diminished anchorage-dependent and -independent cell growth and reduced angiogenic potential. These results therefore demonstrate that AHRR is a putative new tumor suppressor gene in multiple types of human cancers.
Enrique Zudaire, Natalia Cuesta, Vundavalli Murty, Karen Woodson, Lisa Adams, Nieves Gonzalez, Alfredo Martínez, Gopeshwar Narayan, Ilan Kirsch, Wilbur Franklin, Fred Hirsch, Michael Birrer, Frank Cuttitta
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In Silico Identification of an Aryl Hydrocarbon Receptor Antagonist with Biological Activity In Vitro and In Vivo
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Molecular pharmacology | 2014 |
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Biochemical Pharmacology | 2014 |
Regulation of p53-targeting microRNAs by polycyclic aromatic hydrocarbons: Implications in the etiology of multiple myeloma: PAHs AND miRNAs IN MULTIPLE MYELOMA
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Maternal Smoking and DNA Methylation in Newborns: In Utero Effect or Epigenetic Inheritance?
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Blood | 2013 |
Khellin and visnagin differentially modulate AHR signaling and downstream CYP1A activity in human liver cells
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PloS one | 2013 |
Tobacco smoking leads to extensive genome-wide changes in DNA methylation
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PloS one | 2013 |
Association between polymorphisms in the aryl hydrocarbon receptor repressor gene and disseminated testicular germ cell cancer
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Frontiers in Endocrinology | 2013 |
Postnatal stability, tissue, and time specific effects of AHRR methylation change in response to maternal smoking in pregnancy
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Epigenetics : official journal of the DNA Methylation Society | 2013 |
The Ah receptor regulates growth factor expression in head and neck squamous cell carcinoma cell lines: GROWTH FACTOR TARGETS OF AHR
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Shaping the glioma immune microenvironment through tryptophan metabolism
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CNS Oncology | 2012 |
Poor Prognosis of Gastric Adenocarcinoma with Decreased Expression of AHRR
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PloS one | 2012 |
The Aryl Hydrocarbon Receptor Mediates Leflunomide-Induced Growth Inhibition of Melanoma Cells
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Demethylation of the aryl hydrocarbon receptor repressor as a biomarker for nascent smokers
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Src-mediated aryl hydrocarbon and epidermal growth factor receptor cross talk stimulates colon cancer cell proliferation
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Journal of Cancer Epidemiology | 2009 |
Characterization of MCF mammary epithelial cells overexpressing the Arylhydrocarbon receptor (AhR)
PS Wong, W Li, CF Vogel, F Matsumura |
BMC Cancer | 2009 |
The active form of human aryl hydrocarbon receptor (AHR) repressor lacks exon 8, and its Pro 185 and Ala 185 variants repress both AHR and hypoxia-inducible factor
SI Karchner, MJ Jenny, AM Tarrant, BR Evans, HJ Kang, I Bae, DH Sherr, ME Hahn |
Molecular and cellular biology | 2009 |
SUMO modification regulates the transcriptional repressor function of aryl hydrocarbon receptor repressor
M Oshima, J Mimura, H Sekine, H Okawa, Y Fujii-Kuriyama |
The Journal of biological chemistry | 2009 |
Epidermal growth factor-activated aryl hydrocarbon receptor nuclear translocator/HIF-1{beta} signal pathway up-regulates cyclooxygenase-2 gene expression associated with squamous cell carcinoma
KY Chang, MR Shen, MY Lee, WL Wang, WC Su, WC Chang, BK Chen |
The Journal of biological chemistry | 2009 |
Protocadherin PCDH10, Involved in Tumor Progression, is a Frequent and Early Target of Promoter Hypermethylation in Cervical Cancer
G Narayan, L Scotto, V Neelakantan, SH Kottoor, AH Wong, SL Loke, M Mansukhani, B Pothuri, JD Wright, AM Kaufmann, A Schneider, H Arias-Pulido, Q Tao, VV Murty |
Genes, chromosomes & cancer | 2009 |
The aryl hydrocarbon receptor (AhR) pathway as a regulatory pathway for cell adhesion and matrix metabolism
T Kung, KA Murphy, LA White |
Biochemical Pharmacology | 2008 |
Regulation of constitutive and inducible AHR signaling: complex interactions involving the AHR repressor
ME Hahn, LL Allan, DH Sherr |
Biochemical Pharmacology | 2008 |