Functions of IKK alpha in Skin Homeostasis and Skin Tumorigenesis

Division Of Basic Sciences - Nci

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Abstract

miRNAs, which are 19-25-nucleotide noncoding RNAs, regulate the expression of many genes at the post-transcriptional stage by binding to, and destabilizing, mRNAs, thereby blocking protein production. Dicer is an important regulator for miRNA maturation. Recently, our results showed decreased levels of Dicer's protein and RNA in IKKa-null keratinocytes compared to wild-type (WT) keratinocytes, suggesting that IKKa may regulate the expression of Dicer at a transcription level. The Dicer promoter contains two binding sites of Ying Yang 1 (YY1), a transcription factor that can positively or negatively regulate gene expression, depending on which proteins it interacts with. We also found that the Dicer promoter was highly methylated in IKKa-null keratinocytes compared to WT and that IKKa and YY1 formed the complex with the Dicer promoter, and that IKKa deletion increased levels of YY1, EZH2, and H3K27me3 in the complex with the Dicer promoter. This increased complex in IKKa-null keratinocytes is involved in DNA methylation. Furthermore, we found that downregulated Dicer upregulates several miRNAs and one of them targets an inflammasome pathway through a TLR signaling. Our data indicates that IKKalpha deletion enhances or amplifies the bacteria-mediated pathways, promoting skin inflammation, hyperplasia, and skin cancer.