Expression of common chromosomal fragile site genes, WWOX/FRA16D and FHIT/FRA3B is downregulated by exposure to environmental carcinogens, UV, and BPDE but not by IR.
Common chromosomal fragile sites are unstable genomic loci susceptible to breakage, rearrangement, and are highly recombinogenic. Frequent alterations at these loci in tumor cells led to the hypothesis that they may contribute to cancer development. The two most common chromosomal fragile sites FRA16D and FRA3B which harbor WWOX and FHIT genes, respectively, are frequently altered in human cancers. Here we report that environmental carcinogens, ultraviolet (UV) light, and Benzo[a]pyrene diol epoxide (BPDE), significantly downregulate expression of both genes. On the other hand, we observe that ionizing radiation (IR) does not affect expression of these genes, suggesting that the effect of repression exerted by UV and BPDE is not just a consequence of DNA damage but may be a result of different signaling pathways triggered by specific DNA lesions. Such downregulation correlates with an induction of an S-phase delay in the cell cycle. Treatment of UV-irradiated cells with caffeine abrogates the S-phase delay while concomitantly overcoming the repression phenomenon. This suggests the involvement of unique cell cycle checkpoint mechanisms in the observed repression. Therefore, it is hypothesized that protracted downregulation of the putative tumor suppressor genes WWOX and FHIT by environmental carcinogens may constitute an additional mechanism of relevance in the initiation of tumorigenesis.
Thavathiru
Elangovan
E
Department of Carcinogenesis, The University of Texas M. D. Anderson Cancer Center, Science Park-Research Division, Smithville, Texas 78957, USA.
Ludes-Meyers
John H
JH
MacLeod
Michael C
MC
Aldaz
C Marcelo
CM
D015123:7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide / Q000494:pharmacology*; D017766:Acid Anhydride Hydrolases / Q000235:genetics / Q000378:metabolism*; D002274:Carcinogens, Environmental / Q000494:pharmacology*; D045744:Cell Line, Tumor; D043283:Chromosome Fragile Sites / Q000235:genetics*; D015536:Down-Regulation / Q000187:drug effects* / Q000528:radiation effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000528:radiation effects; D006801:Humans; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D010088:Oxidoreductases / Q000235:genetics / Q000378:metabolism*; D011839:Radiation, Ionizing; D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D025521:Tumor Suppressor Proteins; D014466:Ultraviolet Rays; D000074584:WW Domain-Containing Oxidoreductase; D000099170:Bis(5'-adenosyl)triphosphatase
D015123:7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide; D017766:Acid Anhydride Hydrolases; D002274:Carcinogens, Environmental; D009363:Neoplasm Proteins; D010088:Oxidoreductases; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D000074584:WW Domain-Containing Oxidoreductase; D000099170:Bis(5'-adenosyl)triphosphatase; C486071:WWOX protein, human