Late Cornified Envelope Group I, a Novel Target of p53, Regulates PRMT5 Activity

Abstract

p53 is one of the most important tumor suppressor genes involved in human carcinogenesis. Although downstream targets of p53 and their biologic functions in cancer cells have been extensively investigated, it is still far from the full understanding. Here, we demonstrate that Late Cornified Envelope Group I (LCE1) genes, which are located in the LCE gene clusters encoding multiple well-conserved stratum-corneum proteins, are novel downstream targets of p53. Exogenous p53 overexpression using an adenoviral vector system significantly enhanced the expression of LCE1 cluster genes. We also observed induction of LCE1 expressions by DNA damage, which was caused by treatment with adriamycin or UV irradiation in a wild-type p53-dependent manner. Concordantly, the induction of LCE1 by DNA damage was significantly attenuated by the knockdown of p53. Among predicted p53-binding sites within the LCE1 gene cluster, we confirmed one site to be a p53-enhancer sequence by reporter assays. Furthermore, we identified LCE1 to interact with protein arginine methyltransferase 5 (PRMT5). Knockdown of LCE1 by specific small interfering RNAs significantly increased the symmetric dimethylation of histone H3 arginine 8, a substrate of PRMT5, and overexpression of LCE1F remarkably decreased its methylation level. Our data suggest that LCE1 is a novel p53 downstream target that can be directly transactivated by p53 and is likely to have tumor suppressor functions through modulation of the PRMT5 activity.