LSD1 Inhibition Promotes Epithelial Differentiation through Derepression of Fate-Determining Transcription Factors
LSD1 Inhibition Promotes Epithelial Differentiation through Derepression of Fate-Determining Transcription Factors
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DOI：
10.1016/j.celrep.2019.07.058
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发表时间：
2019-08-20
期刊：
影响因子：
8.8
通讯作者：
Capell, Brian C.
中科院分区：
文献类型：
--
作者：
Egolf, Shaun;Aubert, Yann;Capell, Brian C.
自我更新的体细胞组织依赖于染色质修饰酶的适当平衡来协调祖细胞的维持和分化，其破坏可促进癌发生。因此，靶向表观基因组的药物具有显著的治疗潜力。组蛋白去甲基化酶LSD 1（KDM 1A）在许多癌症中过表达，包括上皮癌;然而，它在皮肤中的作用几乎是未知的。在这里，我们表明，LSD 1直接抑制主上皮转录因子，促进分化。LSD 1抑制剂阻断LSD 1与染色质的结合及其催化活性，从而驱动这些命运决定转录因子的H3 K4甲基化和基因转录的显著增加。这导致表皮过早分化和鳞状细胞癌的抑制。总之，这些数据突出了LSD 1在维持表皮祖细胞状态中的作用以及LSD 1抑制剂用于治疗角质形成细胞癌的潜力，角质形成细胞癌的总数超过了所有其他癌症的总和。
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.