Penn Epigenetics Institute, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Department of Dermatology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA.
Department of Dermatology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA.
Cell Rep. 2019 Aug 20;28(8):1981-1992.e7. doi: 10.1016/j.celrep.2019.07.058.
Self-renewing somatic tissues depend upon the proper balance of chromatin-modifying enzymes to coordinate progenitor cell maintenance and differentiation, disruption of which can promote carcinogenesis. As a result, drugs targeting the epigenome hold significant therapeutic potential. The histone demethylase, LSD1 (KDM1A), is overexpressed in numerous cancers, including epithelial cancers; however, its role in the skin is virtually unknown. Here we show that LSD1 directly represses master epithelial transcription factors that promote differentiation. LSD1 inhibitors block both LSD1 binding to chromatin and its catalytic activity, driving significant increases in H3K4 methylation and gene transcription of these fate-determining transcription factors. This leads to both premature epidermal differentiation and the repression of squamous cell carcinoma. Together these data highlight both LSD1's role in maintaining the epidermal progenitor state and the potential of LSD1 inhibitors for the treatment of keratinocyte cancers, which collectively outnumber all other cancers combined.
自我更新的体组织依赖于染色质修饰酶的适当平衡，以协调祖细胞的维持和分化，其破坏会促进癌发生。因此，针对表观基因组的药物具有重要的治疗潜力。组蛋白去甲基酶 LSD1（KDM1A）在许多癌症中过度表达，包括上皮癌；然而，它在皮肤中的作用实际上是未知的。在这里，我们表明 LSD1 直接抑制促进分化的主上皮转录因子。LSD1 抑制剂阻断 LSD1 与染色质的结合及其催化活性，导致 H3K4 甲基化和这些决定命运的转录因子的基因转录显著增加。这导致表皮过早分化和鳞状细胞癌的抑制。这些数据共同强调了 LSD1 在维持表皮祖细胞状态中的作用以及 LSD1 抑制剂治疗角质形成细胞癌的潜力，后者的总数超过了所有其他癌症的总和。
