The project focuses on role of IKKa in skin tumorigenesis. The inflammatory microenvironment promotes skin tumorigenesis. However, the mechanisms of how cells protect themselves from inflammatory signals have yet to be revealed. Downregulation of IKKa promotes skin tumor progression from papillomas to squamous cell carcinomas. 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. However, whether IKKa regulates miRNA during the development of skin tumors remains unknown. Thus, we are addressing this question. The outcome of this study may identify new therapeutic targets for skin tumor treatment. Dicer is an important regulatory 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. Together, our results suggest that IKKa may protect the Dicer promoter from DNA methylation by regulating YY1 transcriptional activity. We are going to identify the molecular mechanism of this regulation in keratinocytes, examine the alterations of miRNAs of Dicer's targets, and further determine the effects of these alterations of miRNAs on skin tumor development.
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