Department of Molecular and Biomedical Pharmacology, University of Kentucky, College of Medicine, Lexington, KY 40506, USA; Markey Cancer Center, University of Kentucky, College of Medicine, Lexington, KY 40506, USA.
Cell Rep. 2013 Oct 17;5(1):224-36. doi: 10.1016/j.celrep.2013.08.030. Epub 2013 Sep 26.
LSD1 is a critical chromatin modulator that controls cellular pluripotency and differentiation through the demethylation of H3K4me1/2. Overexpression of LSD1 has been observed in many types of tumors and is correlated with its oncogenic effects in tumorigenesis. However, the mechanism leading to LSD1 upregulation in tumors remains unclear. Using an unbiased siRNA screening against all the human deubiquitinases, we identified USP28 as a bona fide deubiquitinase of LSD1. USP28 interacted with and stabilized LSD1 via deubiquitination. USP28 overexpression correlated with LSD1 upregulation in multiple cancer cell lines and breast tumor samples. Knockdown of USP28 resulted in LSD1 destabilization, leading to the suppression of cancer stem cell (CSC)-like characteristics in vitro and inhibition of tumorigenicity in vivo, which can be rescued by ectopic LSD1 expression. Our study reveals a critical mechanism underlying the epigenetic regulation by USP28 and provides another treatment approach against breast cancer.
LSD1 是一种关键的染色质调节剂，通过 H3K4me1/2 的去甲基化来控制细胞多能性和分化。在许多类型的肿瘤中都观察到 LSD1 的过表达，并且与肿瘤发生中的致癌作用相关。然而，导致肿瘤中 LSD1 上调的机制尚不清楚。通过针对所有人类去泛素化酶的无偏见 siRNA 筛选，我们鉴定出 USP28 是 LSD1 的真正去泛素化酶。USP28 通过去泛素化与 LSD1 相互作用并稳定 LSD1。USP28 的过表达与多种癌细胞系和乳腺癌样本中的 LSD1 上调相关。USP28 的敲低导致 LSD1 不稳定，从而抑制体外的癌症干细胞（CSC）样特征，并抑制体内的致瘤性，而过表达 LSD1 可以挽救这种抑制作用。我们的研究揭示了 USP28 对表观遗传调控的关键机制，并为乳腺癌提供了另一种治疗方法。
