The H3K27 Demethylase UTX regulates skin carcinogenesis possibly through a HOXB9 pathway
Yang Y, Sarantopoulos C, Peng H, Yin C, Yao Y, Li C, Zhou L, and Mi Q. 163 The H3K27 Demethylase UTX regulates skin carcinogenesis possibly through a HOXB9 pathway. J Invest Dermatol 2019; 139(5):S28.
J Invest Dermatol
The squamous-cell carcinomas (SCC) is one of the most common skin cancer in the United States. The molecular mechanisms that are involved in SCC pathogenesis are still unclear. Ubiquitously Transcribed Tetratricopeptide Repeat on chromosome X (UTX) is a histone demethylase that specifically targets di- and tri-methyl groups on lysine 27 of histone H3 (H3K27me2/3). Recent studies indicate that UTX is involved in tumor development through regulating the H3K27me3 level and HOXB9 signaling pathway. However, it's totally unknown if UTX is involved in SCC development. Here, we tested our hypothesis that UTX may serve as an epigenetic regulator in skin carcinogenesis. We first examined the expression of UTX expression in SCC, and found that the expression of UTX was dramatically decreased in SCC by immunohistochemistry staining, compared to perilesional skin and nevus (N=3). To further investigate the function of UTX specifically in epidermal keratinocytes on skin carcinogenesis in vivo, we next generated the keratinocyte-specific UTX knockout mice by crossing UTX.loxp with K14Cre mice, called K14-Cre/UTXFL/FL KO mice (UTXKO) mice. The mice treated by DMBA at first week, followed by TPA for 24 weeks, were monitored for the papilloma incidence and severity. We found that loss of UTX did not significantly alter the incidence of tumor development, however, significantly enhanced tumor severity with increased tumor number. The RNA sequence analysis from skin tumor lesions indicated that the HOXB9 signaling pathway was significantly increased in UTXKO mice compared to WT mice. Overall, our current findings suggest that UTX is a new epigenetic regulator to control SCC development and may serve as potential therapeutic target for SCC.