Epstein-Barr virus latent membrane protein 1 suppresses the growth-inhibitory effect of retinoic acid by inhibiting retinoic acid receptor-beta2 expression via DNA methylation.
Epigenetic alteration through DNA methylation in retinoic acid receptor-beta2 (RAR-beta2) is common in human tumors including nasopharyngeal carcinoma (NPC); however, the mechanism and its biological significance are unknown. Here, we report that the Epstein-Barr virus (EBV) oncogene product, latent membrane protein 1 (LMP1), induces promoter hypermethylation of RAR-beta2 via up-regulation of DNA methyltransferases 1, 3a, and 3b, leading to decrease in RAR-beta2 expression in NPC cells. In addition, LMP1 abolished the potentials of retinoic acid (RA) to down-regulate Cdk2 and Cdk4 and to up-regulate p16, p21, and p27, resulting in activation of E2F1 in the presence of RA. As a consequence, LMP1 could abrogate the growth-inhibitory effect of RA by releasing cell cycle arrest at G1 phase. Considering that RAR-beta2 is a major executor of the anti-tumor potentials of retinoids, its down-regulation by LMP1 might play an important role during EBV-mediated tumorigenesis.
Seo
So Young
SY
Division of Biological Sciences, College of Natural Sciences, Pusan National University, Busan, Republic of Korea.
Kim
Eun-Ok
EO
Jang
Kyung Lib
KL
D000970:Antineoplastic Agents / Q000037:antagonists & inhibitors*; D045744:Cell Line, Tumor; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000502:physiology; D019175:DNA Methylation; D016193:G1 Phase / Q000187:drug effects; D006801:Humans; D011401:Promoter Regions, Genetic; D018168:Receptors, Retinoic Acid / Q000037:antagonists & inhibitors* / Q000235:genetics; D014212:Tretinoin / Q000037:antagonists & inhibitors*; D014763:Viral Matrix Proteins / Q000502:physiology*
D000970:Antineoplastic Agents; C037662:EBV-associated membrane antigen, Epstein-Barr virus; D018168:Receptors, Retinoic Acid; D014763:Viral Matrix Proteins; C082925:retinoic acid receptor beta; D014212:Tretinoin; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases