The aryl hydrocarbon receptor repressor is a putative tumor suppressor gene in multiple human cancers.
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.
Zudaire
Enrique
E
Angiogenesis Core Facility, NCI, NIH, Gaithersburg, Maryland 20892-4605, USA. zudairee@mail.nih.gov
Cuesta
Natalia
N
Murty
Vundavalli
V
Woodson
Karen
K
Adams
Lisa
L
Gonzalez
Nieves
N
Martínez
Alfredo
A
Narayan
Gopeshwar
G
Kirsch
Ilan
I
Franklin
Wilbur
W
Hirsch
Fred
F
Birrer
Michael
M
Cuttitta
Frank
F
D000818:Animals; D017209:Apoptosis / Q000235:genetics; D002453:Cell Cycle / Q000235:genetics; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D016147:Genes, Tumor Suppressor / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D051379:Mice; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D034741:RNA, Small Interfering / Q000494:pharmacology; D018336:Receptors, Aryl Hydrocarbon / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*
D034741:RNA, Small Interfering; D018336:Receptors, Aryl Hydrocarbon