Department of Pharmacology & Nutritional Sciences, University of Kentucky School of Medicine, Lexington, Kentucky.
Markey Cancer Center, the University of Kentucky, College of Medicine, Lexington, Kentucky.
Mol Cancer Res. 2023 Dec 1;21(12):1303-1316. doi: 10.1158/1541-7786.MCR-23-0169.
Lysine-specific demethylase 1 (LSD1), a critical chromatin modulator, functions as an oncogene by demethylation of H3K4me1/2. The stability of LSD1 is governed by a complex and intricate process involving ubiquitination and deubiquitination. Several deubiquitinases preserve LSD1 protein levels. However, the precise mechanism underlying the degradation of LSD1, which could mitigate its oncogenic function, remains unknown. To gain a better understanding of LSD1 degradation, we conducted an unbiased siRNA screening targeting all the human SCF family E3 ligases. Our screening identified FBXO24 as a genuine E3 ligase that ubiquitinates and degrades LSD1. As a result, FBXO24 inhibits LSD1-induced tumorigenesis and functions as a tumor suppressor in breast cancer cells. Moreover, FBXO24 exhibits an inverse correlation with LSD1 and is associated with a favorable prognosis in breast cancer patient samples. Taken together, our study uncovers the significant role of FBXO24 in impeding breast tumor progression by targeting LSD1 for degradation.
Our study provides comprehensive characterization of the significant role of FBXO24 in impeding breast tumor progression by targeting LSD1 for degradation.
赖氨酸特异性脱甲基酶 1（LSD1）是一种关键的染色质调节剂，通过去甲基化 H3K4me1/2 发挥癌基因作用。LSD1 的稳定性受泛素化和去泛素化等复杂过程的控制。几种去泛素酶可维持 LSD1 蛋白水平。然而，降解 LSD1 的精确机制仍不清楚，因为 LSD1 的降解可以减轻其致癌功能。为了更好地理解 LSD1 的降解，我们针对所有人类 SCF 家族 E3 连接酶进行了无偏见的 siRNA 筛选。我们的筛选鉴定了 FBXO24 作为一种真正的 E3 连接酶，可泛素化和降解 LSD1。结果，FBXO24 抑制 LSD1 诱导的肿瘤发生，并在乳腺癌细胞中作为肿瘤抑制因子发挥作用。此外，FBXO24 与 LSD1 呈负相关，与乳腺癌患者样本的良好预后相关。总之，我们的研究揭示了 FBXO24 通过靶向 LSD1 进行降解在阻碍乳腺癌进展中的重要作用。
我们的研究全面描述了 FBXO24 通过靶向 LSD1 进行降解在阻碍乳腺癌进展中的重要作用。
